1-aminomethyl-1,2,3,4-tetrahydronaphthalenes

ABSTRACT

The present invention provides compounds of the formula ##STR1## or a pharmaceutically acceptable salt thereof wherein R 1  is selected from hydrogen, halo, lower alkyl, lower alkoxy, or thioalkoxy; and R 2  is lower alkoxy; or R 1  and R 2  together form a methylenedioxy or ethylenedioxy ring; R 3  and R 4  are independently selected from hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, (lower alkyl)amino, (lower alkylsulfonyl)amino, and halo; and R 7  is selected from the group consisting of 2- or 3-thienyl, 2- or 3-furyl, and ##STR2## where R 13  and R 14  are independently selected from the group consisting of hydrogen, hydroxy, halogen, amino, lower alkyl, lower alkoxy, lower alkylthio, methylenedioxy, or ethylenedioxy. 
     The compounds of the present invention selectively inhibit α 2  -adrenergic receptors as well as inhibit the uptake of biogenic amines and are thus useful in the treatment of certain cardiovascular and psychiatric disorders.

This is a continuation-in part of U.S. Pat. application Ser. No.07/555501 as PCT/US89/00140, filed Jan. 13, 1989, which is acontinuation in part of U.S. Pat. application Ser. No. 144,364, filedJan. 15, 1988 (now abandoned).

TECHNICAL FIELD

This invention relates to alpha 2 adrenergic antagonists and biogenicamine uptake inhibitors which are useful in the treatment of depression,metabolic disorders (e.g.,obesity or diabetes), glaucoma, migraine andhypertension.

BACKGROUND OF THE INVENTION

The adrenergic nervous system plays a major role in the innervation ofheart, blood vessel and smooth muscle tissue. Compounds capable ofinteracting with receptor sites within the adrenergic nervous system caninitiate a variety of physiological responses, includingvasoconstriction, vasodilation, and increased or decreased heart rate(chronotropic), contractility (inotropic) and metabolic activity. In thepast, various adrenergic compounds have been employed to affect theseand other physiological responses. However, many adrenergic compounds donot possess significant selectivity to enable desirable interactionswith adrenergic receptor sites. That is, these adrenergic compounds donot demonstrate a high degree of specificity for differing receptortypes within the adrenergic nervous system in order to obtain a desiredphysiological response separate from other possible, and perhaps lessdesirable, responses of the system.

DeBernardis, et al., British Patent Application No. 2093837, publishedSept. 8, 1982, discloses aminoalkyl mono or disubstituted1,2,3,4-tetrahydronaphthalenes with adrenergic and/or dopaminergicactivity that are useful as antihypertensive agents. Related compoundsare disclosed in the present invention, however the compounds of thepresent invention have unexpectedly high affinity for alpha 2 receptors.The compounds of the present invention are also biogenic amine uptakeinhibitors. In addition, the compounds of the present invention areuseful as antidepressants and antiglaucoma agents.

DISCLOSURE OF THE INVENTION

It has now been determined that a new class of compounds, as hereindefined, demonstrate an ability to selectively inhibit (i.e.,antagonize) alpha-2-adrenergic receptors which are mainly distributed onthe membranes of central and peripheral adrenergic neurons and on thetissues innervated thereby.

In addition, the compounds of this invention inhibit the uptake ofbiogenic amines. As used herein, the term "biogenic amines" refers toone or more of the compounds selected from the group consisting ofnorepinephrine, serotonin, dopamine and the like.

Through inhibitory interaction with the alpha-adrenergic receptor in theperipheral nervous system, one can modulate the function of adrenergicneurons and hemodynamic equilibrium which is therapeutically useful in amultitude of cardiovascular indications such as hypertension, congestiveheart failure, and a variety of vascular spastic conditions.Furthermore, the alpha adrenergic antagonists and biogenic amine uptakeinhibitors are useful in certain neurological and psychiatric disorderssuch as depression. In addition, the compounds of the present inventionare useful for the treatment of glaucoma.

The present invention includes compounds represented by the formula:##STR3## wherein n is 0 or 1; R₁, R₂, R₃, and R₄ are independentlyselected from hydrogen, hydroxy, amino, alkylamino, alkylsulfonylamino,loweralkyl, loweralkoxy, halo, and thioalkoxy; or R₁ and R₂ or R₂ and R₃taken together can form a methylenedioxy or ethylenedioxy bridge;

R₅ is loweralkyl;

R₆ and R₈ are hydrogen;

R₇ is ##STR4## wherein m is 0, 1 or 2 and X is CH₂, O S or N-CH₃ ; or R₇is ##STR5## wherein s is 0, 1, or 2; Z is C or N; and R₁₁ and R₁₂ areindependently selected from hydrogen, halo, hydroxy, methoxy,thiomethoxy, amino and loweralkyl, or R₁₁ and R₁₂ taken together canform a methylenedioxy or ethylenedioxy bridqe; or R₇ is ##STR6## whereint is 0 or 1; R₉ is hydrogen or loweralkyl; and

R₁₀ is hydrogen, loweralkyl, phenyl, or substituted phenyl wherein thethe phenyl ring is substituted with methylenedioxy, ethylenedioxy orwith one, two or three substituents independently selected fromloweralkyl, halo, hydroxy, loweralkoxy, amino and thioalkoxy; or

R₅ and R₉ taken together form a pyrrolidine ring and then R₆ and R₈ arehydrogen and R₇ is ##STR7## wherein m is 0, 1 or 2 and X is CH₂, O, S orN-CH₃ ; or R₇ is ##STR8## wherein s is 0, 1, or 2; Z is C or N; and R₁₁and R₁₂ are independently selected from hydrogen, halo, hydroxy,methoxy, thiomethoxy, amino and loweralkyl, or R₁₁ and R₁₂ takentogether can form a methylenedioxy or ethylenedioxy bridqe; or R₇ is##STR9## wherein t is 0 or 1; or R₅ and R₉ taken together form apyrrolidine ring and then R is hydrogen and R₇ and R₈ taken togetherform a phenyl, thienyl, furyl or substituted phenyl wherein the phenylring is substituted with methylenedioxy, ethylenedioxy or with one, twoor three substituents independently selected from loweralkyl, halo,hydroxy, loweralkoxy, amino and thioalkoxy; or

R₅ and R₈ taken together form a pyrrolidine ring and then R₉ and R₆ arehydrogen and R₇ is phenyl, thienyl, furyl or substituted phenyl whereinthe phenyl ring is substituted with methylenedioxy, ethylenedioxy orwith one, two or three substituents independently selected fromloweralkyl, halo, hydroxy, loweralkoxy, amino and thioalkoxy; or R₇ andR₉ are hydrogen and R₆ is benzyl, thienylmethyl, furylmethyl orsubstituted benzyl wherein the phenyl ring is substituted withmethylenedioxy, ethylenedioxy or with one, two or three substituentsindependently selected from loweralkyl, halo, hydroxy, loweralkoxy,amino and thioalkoxy; or a pharmaceutically acceptable salt thereof.

It will be appreciated that the compounds of the present inventioncontain one or more asymmetric carbon atoms and it is to be understoodthat the invention includes the diastereomeric mixtures, the racemicmixtures, as well as the optically active compounds. As used herein, thedesignation "R*" or "S*" indicates the absolute configuration of theasymmetric center (i.e., the center is optically active), whereas thedesignation "R" or "S" indicates the relative configuration of theasymmetric center (i.e., the center is racemic).

As used in the structures shown above, the dashed lines mean that eithera single or double bond may exist.

As used herein, the term "loweralkoxy" refers to alkoxy groupscontaining 1 or 2 carbon atoms.

As used herein, the term "thioalkoxy" refers to --SR" wherein R" is aloweralkyl residue.

As used herein, the term "loweralkyl" means straight or branched chainsaturated hydrocarbon radicals having 1 to 3 carbon atoms, such asmethyl, ethyl, n propyl and iso propyl.

As used herein, the term "alkylamino" means --NHR₂₀ or --NR₂₀ R₂₁wherein R₂₀ and R₂₁ are independently selected from loweralkyl.

As used herein, the term "alkylsulfonylamino" means R₂₂ S(O)₂N(R₂₃)-wherein R₂₂ is loweralkyl and R₂₃ is hydrogen or loweralkyl.

As used herein, the term "substituted phenyl" means a phenyl ring withone, two or three substituents independently selected from loweralkyl,halo, hydroxy, loweralkoxy, amino, and thioalkoxy.

As used herein, the term "substituted benzyl" means a benzyl groupwherein the phenyl ring is substituted with one, two or threesubstituents independently selected from halo, loweralkoxy, thioalkoxy,loweralkyl, amino and hydroxy.

As used herein, the term "halo" or "halogen" means fluorine, iodine,bromine or chlorine.

The term "pharmaceutically acceptable salts" refers to thepharmaceutically acceptable, relatively nontoxic, inorganic or organicacid addition salts of the compounds of this invention. These salts canbe prepared in situ during the final isolation and purification of thecompounds, or by separately reacting the free base with a suitableorganic or inorganic acid. Representative salts include thehydrochloride, hydrobromide, sulfate, phosphate, nitrate, bisulfate,acetate, oxalate, valerate, oleate, palmitrate, methanesulfonate,stearate, laurate, borate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, napsylate and the like.It will be apparent to those skilled in the art that, depending upon thenumber of available amino groups for salt formation, the salt of thisinvention can be per N-salts.

The compounds of the present invention can be prepared as illustrated inSchemes 1-4.

As seen in Scheme 1, starting with the appropriately substituted1-tetralone, the dihydro-1-cyanonaphthylene derivative is obtainedeither with trimethylsilyl cyanide or diethylcyanophosphonate. Reductionto the corresponding aminomethyl tetralin is accomplished withRaney-Nickel to afford compound 1. If desired, the 1 carboxylic acidderivative is obtained after reduction with sodium borohydride, followedby hydrolysis, affording 2.

The amine 1 can be alkylated using the appropriate carboxylic acid orester, activated ester or acid halide derivatives thereof, followed byreduction of the resulting amide bond. Acid halide derivatives includethe acid chloride. Esters include the methyl and ethyl esters. Activatedester derivatives include activated esters commonly used by thoseskilled in the art for activating carboxylic acid groups for couplingwith an amine to form an amide bond including, but not limited to,formic and acetic acid derived anhydrides, anhydrides derived fromalkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like,N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derivedesters, N-hydroxybenzotriazole derived esters, 4 nitrophenol derivedesters, 2,4,5-trichlorophenol derived esters and the like. Inparticular, as seen in Scheme 2, compound 1 can be N-alkylated withethyl formate, followed by diborane reduction of the amide, to give 3 orN-alkylated to the mono ethyl derivative with acetic anhydride, followedby diborane reduction, affording 4.

These secondary amines afford the desired products 5 or 6 upondicyclohexylcarbodiimide (DCC) promoted coupling with the appropriatelysubstituted carboxylic acids, followed by reduction of the amideintermediates with lithium aluminium hydride. Alkylation to provide 5 or6 can also be accomplished using carboxylic acid derivatives such asacid halides, esters or activated esters, as described above, followedby reduction of the resulting amide.

As seen in Scheme 3, compound 2, upon coupling with DCC and the desiredpyrrolidine derivative, affords 7 which upon reduction with diboraneaffords the desired pyrrolidine product 9. Carboxylic acid derivativessuch as those described above can also be used in this process.

Alternatively, the pyrrolidine product 12 may be prepared from 2following formation of the acid chloride with oxalyl chloride andsubsequent formation of the carboxamide 8. Treatment of 8 with2,2,5,5-tetramethyl-1-aza-2,5-disilacyclo pentane-1-propyl magnesiumbromide affords 10 upon reduction with sodium borohydride. N-alkylationof the pyrrolidine is accomplished with DCC coupling with a carboxylicacid derivative and diborane reduction to give 12. Carboxylic acidderivatives such as those described above can also be used in thisprocess.

Compound 8, upon reaction with the desired Grignard reagent and then anappropriately substituted amine in the presence of sodiumcyanoborohydride, affords 11. DCC coupling of 11 and the desiredcarboxylic, acid followed by reduction with either diborane or lithiumaluminum hydride, gives the product 13. Carboxylic acid derivatives suchas those described above can also be used in this process.

As seen in Scheme 4, the desired 3-substituted 1-tetralones can besynthesized from the appropriate 1,3-dithiane derivative, which isformed from the corresponding substituted benzaldehyde. Addition of thedithiane anion to various cinnamates or acrylates provides thehomologated ester. Raney nickel reduction and basic hydrolysis, followedby acidic cyclization, affords the desired 3-substituted 1 tetralones,which can be carried on as outlined in schemes 1-3. ##STR10##

The foregoing may be better understood in connection with the followingexamples:

EXAMPLE 1 1-Cyano-6-methoxy-3,4-dihydronaphthalene

To a refluxing benzene solution (60ml) of 6-methoxy-1-tetralone wasadded trimethylsilyl cyanide (TMSCN) (67.5g) and a trace of AlCl₃ orZnI₂. Refluxing was continued for 1 hr., then the solvent removed undervacuum. Isopropyl alcohol saturated with HCl(g) was added and thesolution refluxed for 1 hr. Precipitation began to occur and thereaction was cooled, then evaporated to dryness. Water was added,followed by an ethyl acetate (EtOAc) extraction. The organic layer waswashed in sequence with 1N NaOH, 1N HCl, and brine, separated, dried(MgSO₄), filtered and evaporated. The dark oil was chromatographed onsilica gel and eluted with CH₂ Cl₂, affording 98.5g, 94% yield ofproduct.

EXAMPLE 2 6-Methoxy-1-aminomethyl tetralin hydrochloride

The product (93 g) from Example 1 was hydrogenated at room temperaturewith RaNi (184 g) at 3 atm pressure in the presence of MeOH (900 ml) andNH₃ (100 ml). The solvent was evaporated, H₂ O and KOH added, followedby extraction with ethyl acetate. The organic layer was washed withbrine, separated, dried (MgSO₄), filtered then isopropanol/HCl added.The desired product precipitated, was filtered and dried (87.7 g).

EXAMPLE 3 1-((N-Methylamino)methyl)-6-methoxytetralin hydrochloride

The product from Example 2 was converted to the free base (15q) thendissolved in toluene (40 ml). Ethyl formate (70ml) was added and thereaction refluxed for 2 hr. The solvent was evaporated giving an oil.This was dissolved in dry tetrahydrofuran (THF) (100 ml) and addeddropwise to lithium aluminum hydride (3.23 g) in THF, with cooling. Uponcomplete addition, the reaction was refluxed for 21/2 hr. then stirredan additional 24 hr at room temperature, followed by an additional 3 hrsrefluxing. The mixture was cooled in an ice bath, then quenched with H₂O (3.3 ml), 15% aq. KOH (3.3ml) and H₂ O (9.9ml) added dropwise. Afterstirring for 1 hr at room temperature, the reaction was filtered, andevaporated to dryness. The residue was converted to the HCl salt withethereal/HCl giving 12.9 g desired product.

EXAMPLE 4 N-(6-Methoxy-1,2,3,4-tetrahydro-1-naphthyl)methyl-N-methyl2-thienylacetamide

The product from Example 3 was converted to the free base (6 g) anddissolved in dry tetrahydrofuran (THF) (125 ml). Then 2 thiopheneaceticacid (3.62 g) and 1-hydroxybenzotriazole (5.1 g) was added followed bythe dropwise addition of N,N'-dicyclohexylcarbodiimide (DCC) 6.7 g indry THF (50ml). The reaction was stirred at room temperature overnight,then filtered and evaporated to dryness. The oil was dissolved in EtOAcand upon standing precipitation occurred. This was filtered, and thefiltrate washed with 1N NaOH, then 1N HCl and brine. The organic phasewas dried (MgSO₄), filtered and concentrated to afford the product, 7.4g, 91% yield.

EXAMPLE 5 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-6-methoxytetralin methanesulfonate

The product from Example 4 (7.2 g) was dissolved in dry THF (50ml) thena 1M solution of BH₃ in THF (65 ml) was added dropwise. The reaction wasrefluxed for 3 hrs., cooled, treated with 6N HCl (50 ml) added dropwise,and upon complete addition, refluxed for 2 hrs. The reaction was thenallowed to stand overnight during which time a solid precipitated. Thissolid was filtered and dried giving 7.24 g of the hydrochloride salt,m.p. 211°-213° C. Anal. calcd. for C₁₉ H₂₆ C1NOS: C, 64.83; H, 7.46; N,3.98; Found: C, 64.59; H, 7.40; N, 3.74.

The hydrochloride was converted to the free base and dissolved in EtOAc(50 ml), then methanesulfonic acid (1.1 ml) in EtOAc added. A solidseparated, which was filtered giving the product, m.p. 129°-30° C. Anal.calcd. for C₂₀ H₂₉ NO₄ S₂ : C, 58.35; H, 7.12; N, 3.40. Found: C, 58.23;H, 7.01; N, 3.36.

EXAMPLE 6

Using the product from Example 3 and utilizing the procedures describedin Examples 4 and 5 substituting for the 2-thiopheneacetic acid thedesired readily available carboxylic acid the following compounds wereprepared:

6a) 1-((N-methylamino)methyl-N-(2-(p-fluorophenyl)ethyl))-6-methoxytetralin hydrochloride; m.p. 202°-4° C.

Anal. calcd. for C₂₁ H₂₇ C1FNO: C, 69.30; H, 7.49; N, 3.85. Found: C,69.07; H, 7.43; N, 3.94.

b) 1-((N-methylamino)methyl-N-(2-(m-fluorophenyl)ethyl))-6-methoxytetralin hydrochloride; m.p. 203°-5° C.

Anal. calcd. for C₂₁ H₂₇ C1FNO: C, 69.30; H, 7.49; N, 3.85. Found: C,69.32; H, 7.59; N, 3.60.

c) 1-((N-methylamino)methyl-N-(2-phenylethyl))-6-methoxy tetralinhydrochloride; m.p. 206°-8° C.

Anal. calcd. for C₂₁ H₂₈ C1NO: C, 72.90; H, 8.17; N, 4.05. Found: C,72.70; H, 8.01; N, 3.81.

d) 1-((N-methylamino)methyl-N-(2-(3-thienyl)ethyl))-6-methoxy tetralinhydrochloride; m.p. 215°-16° C.

Anal. calcd. for C₁₉ H₂₆ C1NOS: C, 64.83; H, 7.46; N, 3.98. Found: C,64.88; H, 7.62; N, 3.99.

e) 1-((N-methylamino)methyl-N-(4-(2-thienyl)butyl))-6-methoxy tetralinhydrochloride; m.p. 172°-5° C.

Anal calcd. for C₂₁ H₃₀ C1NOS: C, 66.38; H, 7.96; N, 3.69. Found: C,66.22; H, 7.80; N, 3.24.

f) 1-((N-methylamino)methyl-N-(2-(cyclopentyl)ethyl))-6-methoxy tetralinhydrochloride; m.p. 189°-90° C.

Anal. calcd. for C₂₀ H₃₂ C1NO: C, 71.09; H, 9.54; N, 4.14. Found: C,70.61; H, 9.64; N, 3.97.

g) 1-((N-methylamino)methyl-N-(2-(o-iodophenyl)ethyl))-6-methoxytetralin hydrochloride; m.p. 140°-41° C.

Anal. calcd. for C₂₁ H₂₇ C1INO.1/2 H₂ O: C, 52.46; H, 5.87; N, 2.91.Found: C, 52.34; H, 5.75; N, 2.97.

h) 1-((N-methylamino)methyl-N-(2-(2-tetrahydrothienyl) ethyl)) 6-methoxytetralin hydrochloride; m.p. 163°-64° C.

Anal. calcd. for C₁₉ H₃₀ C1NSO C, 64.11; H, 8.49; N, 3.93. Found: C,63.52; H, 8.54; N, 3.83.

i) 1-((N-methylamino)methyl-N-(3-(2-thienyl)propyl))-6-methoxy tetralinhydrochloride; m.p. 169°-70° C.

Anal calcd. for C₂₀ H₂₈ C1NOS: C, 65.64; H, 7.71; N, 3.83. Found: C,65.51; H, 7.42; N, 3.78.

j) 1-((N-methylamino)methyl-N-(3-phenylpropyl))-6-methoxy tetralinhydrochloride; m.p. 169°-70° C.

Anal. calcd. for C₂₂ H₃₀ C1NO: C, 73.41; H, 8.40; N, 3.89. Found: C,73.32; H, 8.57; N, 3.64.

k) 1-((N-methylamino)methyl-N-(2-(m-methoxyphenyl)-ethyl))-6-methoxytetralin hydrochloride, M⁺ 291.

l) 1-((N-methylamino)methyl-N-(2-(m-pyridyl)ethyl))-6-methoxy tetralindihydrochloride; m.p. 188°-89° C.

EXAMPLE 7 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-6-hydroxytetralin hydrochloride

The product from Example 4 (2.35 g of the HCl salt) was added to CH₂ Cl₂(150 ml) and stirred at -78° C. while BBr₃ (2.2 ml) was added dropwise.Upon complete addition the reaction was allowed to warm to roomtemperature and stirred for 1 hr. After this period, the reaction wascooled to -78° C. and quenched by the careful addition of MeOH. Thereaction was evaporated to dryness then dissolved in MeOH/CH₂ Cl₂ andbrought to pH7 with NH₄ OH. The residue was chromatographed on silicagel and eluted with CH₂ Cl₂ with increasing amounts of MeOH to a finalconcentration of 20% MeOH/80% CH₂ Cl₂. The product was evaporated todryness, dissolved in Et₂ O, then ethereal HCl added. Upon evaporation awhite solid was obtained which was crystallized from EtOAC 95%EtOH-Et₂ Omixture affording the desired product. Anal. calcd. for C₁₈ H₂₄ C1NOS:C, 63.97; H, 7.17; N, 4.15. Found: C, 63.57; H, 7.22; N, 3.98.

EXAMPLE 8 1-((N-Methylamino)methyl-N-(2-(3-thienyl)ethyl))-6-hydroxytetralin hydrochloride

Using the compound from Example 6d with the procedure of Example 7 thedesired compound was obtained m.p. 114°-16° C. Anal. calcd. for C₁₈ H₂₄C1NOS C, 63.97; H, 7.17; N, 4.15. Found: C, 63.57; H, 7.22; N, 3.98.

EXAMPLE 91-((N-Methylamino)methyl-N-(2-(p-fluorophenyl)ethyl))-6-hydroxy tetralinhydrobromide

The product from Example 6a (1.6 g) was added to CH₂ Cl₂ (30 ml) thencooled to -78° C. BBr₃ (1.5 ml) in 5 ml CH₂ Cl₂ was added dropwise, andthe reaction was stirred 3 hrs. At the end of this period, MeOH (10 ml)was carefully added and the solution was evaporated to dryness affordinga brownish residue. This residue was dissolved in CH₃ CN and allowed tostand at room temperature overnight. A solid precipitated and wasfiltered then recrystallized from CH₃ CN affording the desired product,m.p. 129°-31° C. Anal. calcd. for C₂₀ H₂₅ BrFNO: C, 60.91; H, 6.40; N,3.55. Found: C, 60.76; H, 6.42; N, 3.51.

EXAMPLE 101-((N-Methylamino)methyl-N-(2-(m-fluorophenyl)ethyl))-6-hydroxy tetralinhydrochloride

The product from Example 6b (0.75 g) was O-demethylated with BBr₃ (0.7ml) using the procedure of Example 9. However, after quenching thereaction with MeOH the solution was evaporated to dryness thenmethanolic HCl (20 ml) was added. This was heated on a steam bath untilthe volume was reduced to ca. 2-3 ml. The white solid was trituratedwith ethylacetate, filtered and dried giving the product, m.p. 154°-55°C. Anal. calcd. for C₂₀ H₂₅ C1FNO: C, 68.65; H, 7.22; N, 4.00. Found: C,68.32; H, 7.22; N, 3.70.

EXAMPLE 11 1-((N-Methylamino)methyl-N-(2-phenylethyl))-6-hydroxytetralin hydrobromide

Using the product from Example 6c with the procedure of Example 9afforded the product, m.p. 156°-57° C. Anal. calcd. for C₂₀ H₂₆ BrNO: C,63.82; H, 6.98; N, 3.72. Found: C, 63.56; H, 6.84; N, 3.46.

EXAMPLE 121-((N-Methylamino)methyl-N-(2-(N-methyl-2-pyrrolyl)-ethyl))-6-methoxytetralin fumarate

The desired compound (m.p. 145°-6° C.) was obtained using the proceduresof Examples 1-5 but replacing 2-thiopheneacetic acid withN-methyl-2-pyrrolyl acetic acid and then preparing the fumarate salt inplace of the HCl salt. Anal. calcd. for C₂₄ H₃₂ N₂ O₅ : C, 67.24; H,7.53; N, 6.54. Found: C, 66.89; H, 7.54; N, 6.26.

EXAMPLE 13 5-Methoxy-3,4-dihydronaphthalene-1-carbonitrile

5-Methoxy-1-tetralone (8.80 g) was dissolved in 50 ml of anhydrous THFand cooled to 5° C. under N₂ atmosphere. LiCN (0.50g.) was added to thestirred solution, followed by dropwise addition of diethylcyanophosphonate (9.1 ml) over 10 min. After 45 min at 5° C., thereaction was poured into 200 ml H₂ O and extracted with EtOAc (3×100ml). The combined organic extracts were washed with water (3×150 ml),saturated NaCl (150 ml), dried (MgSO₄), and evaporated under reducedpressure. The resulting colorless oil was dissolved in benzene (100 ml)and p-toluenesulfonic acid (0.50 g) was added. The reaction was stirredat reflux for 2 hr, cooled to room temperature, and poured into 5%NaHCO₃ solution (150 ml). The reaction was extracted with Et₂ O (2×100ml) and the combined organic extracts were washed with saturated NaClsolution (150 ml), dried (MgSO₄ ), and evaporated under reduced pressureto yield 9.55 g of a white solid. The product was recrystallized fromMeOH to yield 7.81 g of the product as white needles.

EXAMPLE 14 5-Methoxy-1-aminomethyl tetralin hydrochloride

The product from Example 13 was hydrogenated using the procedure ofExample 2 to give the desired product. Anal. calcd. for C₁₂ H₁₈ C1NO: C,63.30; H, 7.91; N, 6.15. Found: C, 63.13; H, 8.15; N, 6.09.

EXAMPLE 15 1-((N-Ethylamino)methyl)-5-methoxy tetralin hydrochloride

The product from Example 14 was treated with KOH to qive the free base,then reacted with acetic anhydride affording the amide. Anal. calcd. forC₁₄ H₁₉ NO₂ : C, 72.07; H, 8.21; N, 6.00. Found: C, 72.03; H, 8.25; N,6.01. This amide was reduced using the procedure of Example 5 to givethe desired compound. Anal. calcd. for C₁₄ H₂₂ C1NO C, 65.74; H, 8.67;N, 5.48. Found: C, 65.71; H, 8.61; N, 5.47.

EXAMPLE 16 1-((N-Formylamino)methyl)-5-methoxytetralin

The product from Example 14 was converted to its free base (3.4 g) anddissolved into toluene (30 ml). Ethyl formate (5 ml) was added and thereaction stirred at reflux for 5 hr. The solvent was removed to afford asolid. Recrystallization from Et₂ O/CH₂ Cl₂ afforded 3.07 g of desiredproduct. Anal. calcd. for C₁₃ H₁₇ NO₂ ; C, 71.21; H, 7.81; N, 6.39.Found: C, 71.26; H, 7.82; N, 6.41.

EXAMPLE 17 1-((N-Methylamino)methyl)-5-methoxytetralin hydrochloride

The product from Example 16 (3.8 g) in dry THF (80 ml) was treated with1M solution of BH₃ in THF (38 ml). After the addition was complete, thereaction was heated at reflux for 1 hr, followed by cooling. Thereaction was treated with saturated methanolic HCl (30 ml), heated atreflux for 1 hr and concentrated to afford a solid. Crystallization fromEt₂ O/CH₃ OH afforded 4.1 g of desired product. Anal. calcd. for C₁₃ H₂₀C1NO: C, 64.59; H, 8.34; N, 5.79. Found: C, 64.68; H, 8.49; N, 5.78.

EXAMPLE 18N-(5-Methoxy-1,2,3,4-tetrahydro-1-naphthyl)methyl-N-methyl-2-thienylacetamide

The product from Example 17 (1.04 g), 1-hydroxybenzotriazole hydrate(1.51 g) and 2-thiopheneacetic acid (720 mg) in dry THF (30 ml) at 0° C.was treated with dicyclohexylcarbodiimide (1.16 g). The reaction waswarmed to room temperature and stirred for 18 hr. The mixture wasfiltered and concentrated. The residue was dissolved into EtOAc (60 ml)washed with 5% aq. HCl (15 ml), water (15 ml), 10% aq. KOH (15 ml),dried (MgSO₄) filtered and concentrated. Chromatography on SiO₂ afforded1.58 g of product as a viscous oil.

EXAMPLE 19 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-5-methoxytetralin methanesulfonate

The product from Example 18 (1.58 g) in dry THF (10 ml) was slowly addedto a suspension of lithium aluminum hydride (366 mg) in dry THF (30 ml)and the resulting mixture heated at reflux for 1 hr. The reaction wascooled and treated with water (370 uL), 15% aq. KOH (370 uL) and water(1.1 mL). After 30 min, the mixture was filtered and the filtrateconcentrated. Chromatography on SiO afforded 1.02 g of product as aviscous oil. The oil was dissolved into EtOAc(30 ml) and treated with asolution of methanesulfonic acid (300 uL) in i-PrOH(700 uL).Crystallization occurred upon standing to afford 1.17 g of desiredproduct, m.p. 178°-79° C. Anal. calcd. for C₂₀ H₂₉ NO₄ S₂ : C, 58.37; H,7.10; N, 3.40. Found: C, 58.10; H, 7.16; N, 3.39.

EXAMPLE 20

Using the product from Example 17 and utilizing procedures described inExamples 18 and 19 substituting for the 2 thiopheneacetic acid thedesired readily available carboxylic acid the following compounds wereprepared:

20 a) 1-((N-methylamino)methyl-N-2-(2-furyl)ethyl))-5-methoxytetralinmethanesulfonate, m.p. 154°-55° C. Anal. calcd. for C₂₀ H₂₉ NO₅ S: C,60.74; H, 7.39; N, 3.54. Found: C, 60.36; H, 7.45; H, 3.52.

b) 1-((N-methylamino)methyl-N-(2-(p-fluorophenyl) ethyl))5-methoxytetralin methanesulfonate

c) 1-((N-methylamino)methyl-N-(2-(m-fluorophenyl) ethyl)) 5methoxytetralin methanesulfonate, m.p. 180°-181° C. Anal. calcd. for C₂₂H₃₀ FNO₄ S: C, 62.39; H, 7.14; N, 3.31. Found: C, 62.36; H, 7.08; N,3.31.

EXAMPLE 21 1-((N-Methylamino)methyl-N-(2-(2-furyl)ethyl))-6-methoxytetralin hydrochloride

Reacting the product from Example 3 with 2-furylacetic acid using theprocedures of example 18 gave the desired amide. The amide was reducedusing the procedure of example 19 except the hydrochloride salt wasprepared with ethereal HCl in place of methanesulfonic acid, affordingthe compound, m.p. 203°-5° C. Anal. calcd. for C₁₉ H₂₆ C1NO₂ : C, 67.94;H, 7.80; N, 4.17. Found: C, 67.93; H, 7.90; N, 4.07.

EXAMPLE 22 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl)) tetralinhydrochloride

The desired compound was prepared (m.p. 222°-23° C.) using theprocedures described in Examples 1-5 but replacing 6-methoxy-1-tetralonewith 1-tetralone. Anal. calcd. for C₁₈ H₂₄ C1NS: C, 67.16; H, 7.51; N,4.35. Found: C, 66.76; H, 7.82; N, 4.34.

EXAMPLE 231-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-5,6-methylenedioxytetralin hydrochloride

The desired compound was prepared (m.p. 248°-49° C.) using theprocedures described in Examples 1-5 but replacing 6-methoxy-1-tetralonewith 5,6-methylenedioxy-1-tetralone. Anal. calcd. for C₁₉ H₂₄ C1NO₂ S:C, 62.38; H, 6.57; N, 3.83. Found: C, 62.06; H, 6.57; N, 3.56.

EXAMPLE 241-((N-Methylamino)methyl-N-(2-(m-methoxyphenyl)ethyl))-5,6-dimethoxytetralin hydrochloride

The product was obtained (m.p. 160°-61° C.) using the proceduresdescribed in Examples 1-5 but replacing 6-methoxy-1-tetralone with5,6-dimethoxy-1-tetralone, and using 3-methoxyphenylacetic acid, inplace of 2-thiopheneacetic acid. Anal. calcd. for C₂₃ H₃₂ C1NO₃ : C,68.05; H, 7.95; N, 3.45. Found: C, 68.07; H, 7.99; N, 3.24.

EXAMPLE 251-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-6,7-dimethoxy tetralinhydrochloride

The product was obtained (m.p. 149°-50° C.) using the proceduresdescribed in Examples 1-5 but replacing 6-methoxy-1-tetralone with6,7-dimethoxy-1-tetralone. Anal. calcd. for C₂₀ H₂₈ C1NO₂ S: C, 62.89;H, 7.39; N, 3.67. Found: C, 62.87; H, 7.23; N, 3.54.

EXAMPLE 261-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-6,8-dimethoxy tetralinhydrochloride

The product was obtained (m.p. 210°-12° C.) using the proceduresdescribed in Examples 1-5 but replacing 6-methoxy-1-tetralone with6,8-dimethoxy-1-tetralone. Anal. calcd. for C₂₀ H₂₈ C1NO₂ S: C, 62.89;H, 7.39; N, 3.67. Found: C, 62.55; H, 7.50; N, 3.51.

EXAMPLE 27 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-7-methoxytetralin hydrochloride

The product was obtained (m.p. 180°-1° C.) using the proceduresdescribed in Examples 1-5 but replacing 6-methoxy-1-tetralone with7-methoxy-1-tetralone Anal. calcd. for C₁₉ H₂₆ C1NOS: C, 64.84; H, 7.45;N, 3.98. Found: C, 64.74; H, 7.28; N, 3.88.

EXAMPLE 28 1-((N-Methylamino)methyl-N-(2-phenylethyl))-7-methoxytetralin hydrochloride

The product was prepared (m.p. 178°-79° C.) using the proceduresdescribed in Examples 1-5 but replacing 6-methoxy 1-tetralone with7-methoxy-1-tetralone, and using phenylacetic acid, in place of 2thiopheneacetic acid. Anal. calcd. for C₂₁ H₂₈ C1NO; C, 72.92; H, 8.16;N, 4.05. Found: C, 72.27; H, 8.09; N, 3.87.

EXAMPLE 29 5,6-Ethylenedioxy-1-tetralone

5,6-Dihydroxy-1-tetralone (6 g) was heated at 125° C. with1,2-dichloroethane (7 ml) and K₂ CO₃ (14 g) in DMSO (70 ml) under N₂ for45 min. The reaction was quenched with ice water then extracted with Et₂O. The aqueous layer was removed, then EtOAc added to the remainingorganics. This solution was dried (MgSO₄), filtered and evaporated toqive the desired product.

EXAMPLE 301-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-5,6-ethylenedioxytetralin hydrochloride

The product was prepared (m.p. 205°-6° C.) using the proceduresdescribed in Examples 1-5 but replacing 6-methoxy-1-tetralone with theproduct from Example 29. Anal. calcd. for C₂₀ H₂₅ C1NO₂ S: C, 63.39; H,6.65; N, 3.70. Found: C, 62.96; H, 6.99; N, 3.66.

EXAMPLE 31 6-Thiomethyl-1-tetralone

6-Hydroxy-1-tetralone (16.2 g) prepared from 6-methoxy 1-tetralone andAlCl₃, was dissolved in dry dimethylformamide (DMF)(50 ml) and addeddropwise to a suspension of 4 g NaH (60% in mineral oil) and dry DMF(200 ml) over 30 min. Then, dimethylthiocarbamyl chloride (14.8 g) wasadded and the reaction heated at 85° C. for 4 hrs. The reaction waspoured onto ice and extracted with CH₂ Cl₂ (150 ml). The CH₂ Cl₂ layerwas washed with 10% aq. NaOH, then saturated NaCl solution. The organiclayer was separated, dried (Na₂ SO₄), filtered and evaporated giving atan solid (18.1 g). This was added to mineral oil (100 ml) and heated at270° C. for 2 hrs, then cooled. Cyclohexane (500 ml) was added and asolid separated (14.3 g). This product was added to NaOH (10 g) and MeOH(150 ml) and refluxed 2 hrs. The reaction was cooled, then methyliodide(9.94 g) was added followed by refluxing for 2 hrs. The solvents wereremoved affording the desired product (11 g), M⁺ 192.

EXAMPLE 32 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-6-thiomethyltetralin hydrochloride

The product was prepared (m.p. 206°-7° C.) using the proceduresdescribed in Examples I 5 but replacing 6-methoxy-1-tetralone with theproduct of Example 31. Anal. calcd. for C₁₉ H₂₅ C1NS₂. 1/2 H₂ O: C,60.69; H, 6.97; N, 3.73. Found: C, 60.76; H, 7.12; N, 3.64.

EXAMPLE 331-((N-Methylamino)methyl-N-(2-(m-fluorophenyl)ethyl))-5,6-dimethoxy-8-methyltetralin hydrochloride

The product was obtained (m.p. 184°-86° C.) using the proceduresdescribed in Examples 1-5 but replacing 6-methoxy 1-tetralone with5,6-dimethoxy-8-methyl-tetralone and using 3-fluorophenylacetic acid, inplace of 2-thiopheneacetic acid. Anal. calcd for C₂₃ H₃₁ C1FNO₂ : C,67.72; H, 7.66; N, 3.43. Found: C, 67.31; H, 7.88; N, 3.37.

EXAMPLE 341-((N-Methylamino)methyl-N-(2-(m-fluorophenyl)ethyl))-5,6-dihydroxy-8-methyltetralin hydrobromide

Using the product of Example 33 and the procedure of Example 9 thedesired compound was obtained m.p. (129°-30° C.). Anal. calcd. for C₂₁H₂₇ BrFNO₂.1/2H₂ O: C, 58.20; H, 6.40; N, 3.23. Found: C, 58.45; H,6.33; N, 3.02.

EXAMPLE 35 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))5,6-dimethoxy-8-methyl tetralin hydrochloride

The product was obtained (M⁺ 359) using the procedures described inExamples 1-5 but replacing 6-methoxy-1-tetralone with5,6-dimethoxy-8-methyl-1-tetralone.

EXAMPLE 361-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-5-methoxy-8-methyltetralin hydrochloride

The product was obtained (m.p. 205°-7° C.) using the proceduresdescribed in Examples 1-5 but replacing 6methoxy-1-tetralone with5-methoxy-8-methyl-1-tetralone. Anal. calcd. for C₂₀ H₂₈ C1NOS; C,65.64; H, 7.71; N, 3.83. Found: C, 65.36; H, 7.90; N, 3.77.

EXAMPLE 37

1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-5-methoxy indanehydrochloride

The product was obtained (m.p. 197°-99° C.) using the proceduresdescribed in Examples 1-5 but replacing 6-methoxy-1-tetralone with5-methoxy-1-indanone. Anal calcd. for C₁₈ H₂₄ C1NSO: C, 63.98; H, 7.16;H, 4.15. Found: C, 64.36; H, 7.19; N, 4.00.

EXAMPLE 38 6-Methoxy-7-methyl-1-tetralone

3-Methoxy-4-methylbenzoic acid (30 g) was reduced to the benzylicalcohol with _(BH3) in THF (181 ml of 1 M solution). Oxidation of thisproduct (28.7 g) with pyridinium chlorochromate (71g) gave thebenzaldehyde derivative (21.3 g). Treatment of this alde hyde (19.6 g)with BrPh P(CH ) COOH (54.5 g) under Wit tig conditions afforded4-(3-methoxy-4-methylphenyl)-3-butene carboxylic acid (26.9 g).Catalytic reduction of this product followed by polyphosphoric acid(PPA) cyclization gave the desired tetralone.

EXAMPLE 391-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-6-methoxy-7-methyltetralin hydrochloride

The product was obtained (m.p. 173° 4° C.) using the proceduresdescribed in Examples 1-5 but replacing 6-methoxy-1-tetralone with theproduct of Example 38. Anal. calcd. for C₂₀ H₂₈ NOS: C, 65.64; H, 7.71;H, 3.83. Found: C, 65.47; H, 7.56; N, 3.66.

EXAMPLE 40 1-((N-Ethylamino)methyl)-6-methoxy tetralin hydrochloride

Using the product of Example 2 and the procedure of Example 15 affordedthe desired compound.

EXAMPLE 41 1-((N-Ethylamino)methyl-N-(2-(2-thienyl)ethyl))-6-methoxytetralin hydrochloride

Using the product of Example 40 and the procedures of Examples 4 and 5gave the desired compound m.p. 184°-85° C. Anal. calcd. for C₂₀ H₂₈C1NOS: C, 65.64; H, 7.71; N, 3.83. Found: C, 65.48; H, 7.75; N, 3.79.

EXAMPLE 421-((N-Ethylamino)methyl-N-(2-(m-fluorophenyl)ethyl))-6-methoxy tetralinhydrochloride

Using the product of Example 40 and the procedure of Examples 4 and 5replacing 2-thiopheneacetic acid with m fluoroacetic acid gave thedesired compound, m.p. 153°-54° C. Anal. calcd. for C₂₂ H₂₉ C1FNO: C,70.37; H, 7.73; N, 3.71. Found: C, 70.37; H, 7.93; N, 3.70.

EXAMPLE 43 1-((N-Ethylamino)methyl-N-(2-(2-furyl)ethyl))-6-methoxytetralin hydrochloride

Using the product of Example 40 and the procedure of Examples 18 and 19,replacing 2-thiopheneacetic acid with 2 furylacetic acid and replacingthe methanesulfonic acid with ethereal HCl gave the compound, m.p.176°-7° C. Anal. calcd. for C₂₀ H₂₈ C1NO₂ : C, 68.65; H, 8.07; N, 4.00.Found: C, 68.58; H, 8.12; N, 4.00.

EXAMPLE 44 1-((N-Ethylamino)methyl-N-(2-(3-thienyl)ethyl))-6-methoxytetralin hydrochloride

Using the product of Example 40 and the procedure of Examples 4 and 5replacing 2-thiopheneacetic acid with 3-thiopheneacetic acid gave thecompound, m.p. 159°-60° C. Anal. calcd. for C₂₀ H₂₈ C1NOS.1/4 H₂ O: C,64.84; H, 7.75; N, 3.78. Found: C, 64.93; H, 7.63; N, 3.77.

EXAMPLE 45 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-6-methoxyindane hydrochloride

Using the procedures described in Examples 1-5 but replacing6-methoxy-1-tetralone with 6-methoxy-1-indanone gave the product, m.p.176°-7° C. Anal. calcd. for C₁₈ H₂₄ C1NSO: C, 63.98; H, 7.16; N, 4.15.Found: C, 63.73; H, 7.22; N, 4.13.

EXAMPLE 46 6-Chloro-3,4-dihydronaphthalene-1-carbonitrile

Using the procedure of Example 13 replacing 5-methoxy-1-tetralone with6-chloro-1-tetralone afforded the desired product.

EXAMPLE 47 6-Chloro-1-aminomethyl tetralin hydrochloride

The product from Example 46 was catalytically reduced with Pt₂ O at 4atms. pressure in EtOH and HCl, affording the desired product.

EXAMPLE 48 1-((N-Methylamino)methyl)-6-chloro tetralin hydrochloride

Using the product of Example 47 and the procedure of Example 3 gave thedesired compound.

EXAMPLE 49 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-6-chlorotetralin hydrochloride

Using the product from Example 48 and the procedures of Examples 4 and 5afforded the desired compound, m.p. 233°-34° C. Anal. calcd. for C₁₈ H₂₃Cl₂ NS: C, 60.67; H, 6.46; N, 3.93. Found: C, 60.61; H, 6.54; N, 3.90.

EXAMPLE 501-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl)-6-fluoro-tetralinhydrochloride

Using the procedures described in Example 13, then in Examples 46 48replacing 6 chloro 1 tetralone with 6-fluoro-1 tetralone gave1-(N-methylamino) methyl-6-fluoro tetralin hydrochloride. Using thisproduct and following the procedures of Examples 4 and 5 gave thedesired compound, m.p. 225°-27° C. Anal. calcd. for C₁₈ H₂₃ C1FNS: C,63.62; H, 6.77; N, 4.12. Found: C, 63.93; H, 7.05; N, 4.11.

EXAMPLE 51 5-Bromo1-tetralone

To a benzene solution (60 ml) of 4-(o-bromophenyl) butyric acid (5 g)was added oxalyl chloride (3.6 ml) and the reaction refluxed for 11/2hrs. The solution was evaporated to dryness, the residue was dissolvedin CH₂ Cl₂ (50 ml) then cooled to 0° C., followed by the addition ofAlCl₃ (3.1 g). The mixture was stirred at 0° C. warming to roomtemperature overnight. The reaction was poured onto ice, then extractedwith CH₂ Cl₂. The organic layer was separated, washed with 1N NaOH, thenbrine, separated, dried (MgSO₄), filtered and evaporated affording thedesired product (4.26 g).

EXAMPLE 52 5-Bromo-1,2,3,4-tetrahydronaphthalene-1-carbonitrile

Using the product from Example 51 (10 g) and the procedure of Example 1gave 5 bromo 3,4 dihydronaphthalene 1-carbonitrile (8.5g). This wasreduced to the desired product with NaBH (8.5 g) in ethanol (165 ml),under reflux conditions for 2 hrs.

EXAMPLE 53 5-Bromo-1-aminomethyl tetralin hydrochloride

The product from Example 52 (5 g) was reduced with diborane as inExample 5 and afforded the desired product after recrystallization fromEtOH.

EXAMPLE 54 1-((N-Methylamino)methyl)-5-bromo tetralin hydrochloride

The product from Example 53 was reacted as in the procedure described inExample 3 and gave the desired compound, m.p. 224°-226° C. Anal. calcd.for C₁₂ H₁₇ BrC1N: C, 49.59; H, 5.90; H, 4.82. Found: C, 49.73; H, 5.97;N, 4.81.

EXAMPLE 55 1-((N-Methylamino)methyl-N-(2-(2-furyl)ethyl))-5-bromotetralin methanesulfonate

Reacting the product of Example 54 with 2-furylacetic acid using theprocedure of Example 4 gave the desired amide. This amide was reducedusing the procedure of Example 19 giving the desired compound, m.p.98°-99° C. Anal. calcd. for C₁₉ H₂₆ BrNO₄ S: C, 51.35; H, 5.90; N, 3.15.Found: C, 51.75; H, 6.00; N, 3.14.

EXAMPLE 56 1-((N-Methylamino)methyl-N-(2-(2-furyl)ethyl))-6-bromotetralin methanesulfonate

Using the procedures described in examples 52-55 but replacing 5-bromo 1tetralone with 6-bromo 1-tetralone afforded the desired compound, m.p.95°-97° C. Anal. calcd. for C₁₉ H₂₆ BrNO₄ S: C, 51.35; H, 5.90; N, 3.15.Found: C, 50.96; H, 5.93; N, 3.06.

EXAMPLE 57 1-((N-Propylamino)methyl)-6-methoxy tetralin hydrochloride

The product from Example 2 was reacted as in Example 15 but replacingacetic anhydride with propionic anhydride and gave the desired product.

EXAMPLE 58 1-((N-Propylamino)methyl)-N-(2-(2-thienyl)ethyl))-6-methoxytetralin hydrochloride

Using the product of Example 57 and the procedure of Examples 4 and 5gave the compound (amorphous). Anal. calcd. for C₂₁ H₃₀ C1NOS.1/4 H₂ O:C, 66.60; H, 8.00; N, 3.64. Found: C, 65.78; H, 7.78; N, 3.59.

EXAMPLE 59 1-((N-Methylamino)methyl)-N-(2-(2-thienyl)ethyl))-5-fluoroindane hydrochloride

Using the procedures described in Example 13, and 46-48 but replacingthe 6 methoxy 1 tetralone with 5-fluoro-1-indanone gave the product,m.p. 200°-2° C. Anal. calcd. for C₁₇ H₂₁ C1FNS: C, 62.66; H, 6.50; N,4.30. Found: C, 62.37; H, 6.45; N, 3.98.

EXAMPLE 60 5-Hydroxy-6-iodo-1-indanone

5-Hydroxy-1 indanone (1.48 g),-N-iodosuccinimide (2.25 g) and CH₃ CN (20ml) were stirred at room temperature overnight. The solution wasevaporated to dryness, slurried with EtOAc, then filtered. The filtratewas evaporated to dryness and the solid recrystallized from CH₃ CNaffording the desired compound (0.92 g), m.p. 114°-15° C.

EXAMPLE 61 5-Methoxy-6-iodo-1-indanone

The product of Example 60 was added to methyl ethyl ketone (50 ml), K₂CO₃ (5 g) and methyl iodide (5 ml) then heated at reflux for 41/2 hrs.The reaction was cooled, H₂ O added, followed by an EtOAc extraction.The organic layer was separated, washed with brine, dried (Na₂ SO₄),filtered and evaporated. Trituration of the residue afforded the desiredcompound after filtration, m.p. 129°-30° C.

EXAMPLE 621-((N-Methylamino)methyl)-N-(2-(2-furyl)ethyl))-5-methoxy-6-iodo indanemethanesulfonate

Using the product from Example 61 and the procedures described inExamples 13, 14 and 16-19 replacing 2-thiopheneacetic with 2 furylaceticacid afforded the desired product.

EXAMPLE 63 1-((N-Propylamino)methyl)-5,6-dimethoxy tetralinhydrochloride

Using the procedure of Example 57 but replacing 6-methoxy-1 tetralonewith 5,6-dimethoxy 1 tetralone gave the desired product.

EXAMPLE 641-((N-Propylamino)methyl-N-(2-(p-fluorophenyl)ethyl))-5,6-dihydroxytetralin hydrobromide

Using the product of Example 63 and the procedures described in Examples4 and 5 replacing the 2-thiopheneacetic acid with 4 fluorophenylaceticacid gave1-((N-propylamino)methyl-N-(2-(p-fluorophenyl)ethyl))-5,6-dimethoxytetralin hydrochloride. This product was reacted as described in Example9 to give the desired product, m.p. 212°-14° C. Anal. calcd. for C₂₂ H₂₉BrFNO₂ : C, 60.27; H, 6.68; N, 3.20. Found: C, 60.26; H, 6.58; N, 3.19.

EXAMPLE 65 1-((N-Methylamino)methyl-N-(2-(m-nitrophenyl)ethyl))-tetralinhydrochloride

Using the procedures described in Examples 1-5 but replacing 6methoxy-1-tetralone with 1-tetralone and replacing 2-thiopheneaceticacid with 3-nitrophenylacetic acid gave the desired compound.

EXAMPLE 66 1-((N-Methylamino)methyl-N-(2-(m-aminophenyl)ethyl))-tetralindihydrochloride

The product from Example 65 (3 g) was catalytically reduced with 5% Pd/Cat 3 atms. pressure in MeOH (95 ml) and CHCl₃ (5 ml) affording thedesired amorphous dihydrochloride. Anal. calcd. for C₂₀ H₂₇ Cl₂ N.1/2 H₂O: C, 63.81; H, 7.78; N, 7.44. Found: C, 63.35; H, 7.67; N, 7.38.

EXAMPLE 671-((N-Methylamino)methyl-N-(2-(m-aminophenyl)ethyl))-6-methoxy tetralindihydrochloride

Using the product of Example 3 and the procedures of Example 4, 5 and 66the product was obtained, after recrystallization from EtOAc/EtOH. Anal.calcd. for C₂₁ H₃₀ Cl₂ N₂ O.1/2 H₂ O: C, 62.05; H, 7.70; N, 6.89. Found:C, 62.15; H, 7.83; N, 6.51.

EXAMPLE 681-((N-Methylamino)methyl-N-(2-(m-aminophenyl)ethyl))-6-hydroxy tetralindihydrobromide

The product from Example 67 (1.1 g) was reacted with BBr₃ (1.4 ml) as inthe procedure of Example 9 and gave the desired product. Anal. calcd.for C₂₀ H₂₈ Br₂ N₂ O: C, 61.21; H, 7.46; N, 7.14. Found: C, 60.75; H,7.45; N, 6.89.

EXAMPLE 69 1-((N-Methylamino)methyl-N-(2-(m-aminophenyl)ethyl))-6-ethoxytetralin dihydrochloride

Using the procedures described in Examples 1-5 but replacing6-methoxy-1-tetralone with 6-ethoxy-1-tetralone and replacing2-thiopheneacetic acid with 3-nitrophenylacetic acid gave the nitroderivative which was reduced as in Example 66. The product was obtainedas an amorphous solid. Anal. calcd. for C₂₂ H₃₂ Cl₂ N₂ O.11/2 H₂ O: C,62.84; H, 7.93; N, 6.66. Found: C, 63.06; H, 7.82; N, 6.47.

EXAMPLE 701-((N-Methylamino)methyl-N-(2-(m-fluorophenyl)ethyl))-tetralinhydrochloride

Using the procedures described in Examples 1-5 but replacing6-methoxy-1-tetralone with 1-tetralone and replacing 2-thiopheneaceticacid with m fluorophenyl acetic acid gave the desired product, m.p.198°-99° C. Anal. calcd. for C₂₀ H₂₅ C1FN: C, 71.94; H, 7.56; N, 4.20.Found: C, 72.33; H, 7.53; N, 3.86.

EXAMPLE 71 1-((N-Ethylamino)methyl-N (2-(2-furyl)ethyl))-5-methoxytetralin methanesulfonate

Using the product (free base) of Example 15 and the procedures describedin Examples 18 and 19 but replacing 2-thiopheneacetic acid with2-furylacetic acid gave the desired compound.

EXAMPLE 72 1-((N-Ethylamino)methyl-N-(2-(m-fluorophenyl)ethyl))-5-methoxy tetralin hydrochloride

Using the product (free base) of Example 15 and the procedures describedin Examples 18 and 19 but replacing 2-thiopheneacetic acid withm-fluorophenyl acetic acid gave the desired compound, m.p. 177°-78° C.Anal. calcd. for C₂₂ H₂₉ C1FNO: C, 69.72; H, 7.73; N, 3.71. Found: C,69.96; H, 7.96; N, 3.66.

EXAMPLE 73 1-((N-Ethylamino)methyl-N-(2-(2-thienyl)ethyl))-5-methoxytetralin hydrochloride

Using the product (free base) of Example 15 and the procedures describedin Examples 18 and 19 the desired compound was obtained, m.p. 149°-151°C. Anal. calcd. for C₂₀ H₂₈ C1NOS: C, 65.64; H, 7.71; H, 3.83. Found: C,65.86; H, 8.00, N, 3.84.

EXAMPLE 74 6-Fluoro-1-aminomethyl-3,4-dihydronaphthalene hydrochloride

6-Fluorotetralone (8.2 g), and TMSCN (13.4 ml) in 15 ml benzenecontaining a trace of AlCl₃ or ZnI₂ was heated at 60°-65° C. for 61/2hrs. The reaction was added to Et₂ O (50 ml) then added dropwise to Et₂O (350 ml) containing lithium aluminum hydride (3.8 g) under N₂. Uponcomplete addition, the mixture was gently refluxed for 5 hrs followed bystirring at room temperature overnight. The reaction was quenched by thesuccessive addition of EtOAc (12 ml), H₂ O (4 ml), 15% aq. KOH (4 ml)and H₂ O (12 ml). After the quenching the mixture was stirred at roomtemperature for 1 hr, followed by the addition of anhydrous Na₂ SO₄ withan additional 1/2 hr stirring. The reaction was filtered, ethereal HClwas added to the filtrate and the resulting precipitate filteredaffording a product mp 177°-83° C. This was added to a isopropyl alcoholsaturated with HCl (300 ml) and heated for 41/2 hrs. The solution wascooled and evaporated to dryness and gave the desired compound, m.p.200°-203° C.

EXAMPLE 75 6-Fluoro-1-aminomethyl-1,2,3,4-tetrahydronaphthalenehydrochloride

The product from Example 74 was reduced as in Example 2 but replacingthe NH₃ with acetic acid and afforded the desired compound, m.p.236°-38° C.

EXAMPLE 76 1-((N-Isopropylamino)methyl)-6-fluoro-tetralin hydrochloride

The product from Example 75 (1.5 g) was added to a solution of acetone(25 ml) and MeOH (25 ml) then 95% sodium cyanoborohydride (1.32 g) wasadded in portions. The pH of the reaction was adjusted to ca. pH 5 aftercomplete addition of the NaBH₃ CN. The reaction was then stirred at roomtemperature for 8 hrs. The reaction was evaporated to dryness, thendilute HCl and CH₂ Cl₂ (50 ml) was added. The aqueous layer wasseparated, basified then CH₂ Cl₂ added. The organic layer was separated,dried (MgSO₄), filtered and evaporated. The residue was taken up in Et₂O (300 ml) then ethereal HCl added. The resulting precipitate wasfiltered and recrystallized from EtOAc/MeOH giving the desired compound,m.p. 212°-14° C.

EXAMPLE 77 1-((N-Isopropylamino)methyl-N-(2-(2-furyl)ethyl))-6-fluorotetralin fumarate

The product (free base) of Example 76 was reacted as described inExamples 18 and 19 but replacing 2-thiopheneacetic acid with2-furylacetic acid and gave the desired product after formation of thefumarate salt, m p. 138°-39° C. Anal. calcd. for C₂₄ H₃₀ FNO₅ : C,66.80; H, 7.01; N, 3.25. Found: C, 66.36; H, 6.89; N, 3.20.

EXAMPLE 78 1-((N-Isopropylamino)methyl)-5-fluoro tetralin hydrochloride

Following the procedures described in Examples 74-76 but replacing 6fluoro 1 tetralone with 5-fluoro-1-tetralone afforded the desiredproduct.

EXAMPLE 79 1-((N-Isopropylamino)methyl-N-(2-(2-furyl)ethyl))-5-fluorotetralin methanesulfonate

The product (free base) of Example 78 was treated as described inExamples 18 and 19 but replacing 2-thiopheneacetic acid with 2furylacetic acid giving the desired compound.

EXAMPLE 801-((N-Methylamino)methyl-N-(2-(1,4-benzodioxan)ethyl))-6,8-dimethoxytetralin hydrochloride

Starting with 1-((N-methylamino)methyl)-6,8-dimethoxy tetralin and usingthe procedures described in examples 4 and 5 but replacing2-thiopheneacetic acid with 1,4-benzodioxanacetic acid gave the desiredproduct, m.p. 210°-13° C. Anal. calcd. for C₂₄ H₃₂ C1NO₄ : C, 66.42; H,7..43; N. 3.23. Found: C, 66.29; H, 7.37; N, 3.18.

EXAMPLE 81 1-((N-Methylamino)methyl-N-(3-phenylpropyl))-6- hydroxytetralin hydrochloride

Using the product from Example 6j and the procedure of Example 10 gavethe desired compound, m.p. 120°-122° C. Anal. calcd. for C₂₁ H₂₈C1NO.1/2 H₂ O: C, 71.07; H, 8.24; N, 3.95. Found: C, 70 86; H, 8.08; N,3.80.

EXAMPLE 821-((N-Methylamino)methyl-N-(2-(m-hydroxyphenyl)ethyl))-6-hydroxytetralin hydrochloride

Using the product from example 6k and the procedure described in Example10 the desired compound was obtained as an amorphous solid. Anal. calcd.for C₂₀ H₂₆ C1NO 2H₂ O: C, 62.57; H, 7.88; N, 3.65. Found: C, 62.35; H,7.26; N, 3.43.

EXAMPLE 831-((N-Methylamino)methyl-N-(2-(m-hydroxyphenyl)ethyl))-6-methoxytetralin hydrochloride

Using the product from Example 3 and the procedure of Example 4replacing the 2-thiopheneacetic acid with m-acetoxyphenylacetic acidgave the corresponding amide. Using this amide and the proceduredescribed in Example 5 afforded the desired compound as an amorphoussolid. Anal. calcd. for C₂₁ H₂₈ C1NO₂.H₂ O C, 66.39; H, 7.96; N, 3.69.Found: C, 66.59; H, 7.71; N, 3.65.

EXAMPLE 841-((N-Methylamino)methyl-N-(2-(m-fluorophenyl)ethyl))-5,6-dimethoxytetralin hydrochloride

The product was obtained (m.p. 200°-201° C.) using the proceduresdescribed in Examples 1-5 but replacing 6-methoxy-1-tetralone with5,6-dimethoxy-1-tetralone and using 3-fluorophenylacetic acid in placeof 2-thiopheneacetic acid, m.p. 200 201° C. Anal. calcd. for C₂₂ H₂₉FC1NO₂ : C, 67.08; H, 7.42; N, 3.56. Found: C, 66.69; H, 7.47; N, 3.47.

EXAMPLE 851-((N-Methylamino)methyl-N-(2-(m-fluorophenyl)ethyl))-5,6-dihydroxytetralin hydrochloride

Using the product of Example 84 and the procedures described in Examples9 and 10, the desired compound was obtained, m.p. 158°-60° C. Anal.calcd. for C₂₀ H₂₅ FC1NO₂.H₂ O: C, 62.57; H, 7.09; N, 3.65. Found: C,62.41; H, 6.59; N, 3.74.

EXAMPLE 861-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-5,6-dimethoxy tetralinhydrochloride

Using the procedures described in Examples 1-5 but replacing6-methoxy-1-tetralone with 5,6-dimethoxy-1-tetralone gave the product,m.p. 235°-6° C. Anal. calcd. for C₂₀ H₂₈ C1NO₂ S: C, 62.89; H, 7.39; N,3.67. Found: C, 62.88; H, 7.68; N, 3.67.

EXAMPLE 871-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-5,6-dihydroxy tetralinhydrochloride

Using the product of Example 86 and the procedures described in Examples9 and 10 the desired product was afforded Anal. calcd. for C₁₈ H₂₄ C1NO₂S: C, 61.09; H, 6.84; N, 3.96. Found: C, 61.00; H, 7.14; N, 3.65.

EXAMPLE 88 1-((N-Methylamino)methyl-N-(2-phenethyl)) tetralinhydrochloride

Using the procedures described in Examples 1-5 but replacing6-methoxy-1-tetralone with 1-tetralone and replacing 2-thiopheneaceticacid with 2-phenylacetic acid gave the product, m.p. 207°-208° C. Anal.calcd. for C₂₀ H₂₆ ClN: C, 76.05; H, 8.30; N, 4.43. Found: C, 75.77; H,8.67; N, 4.58.

EXAMPLE 891-((N-Methylamino)methyl-N-(2-(3-nitro-4-hydroxyphenyl)-ethyl))-6-methoxytetralin hydrochloride

Using the procedures described in Examples 1-5 but replacing2-thiopheneacetic acid with 4-acetoxy-3-nitrophenylacetic acid gave thedesired product. Anal. calcd. for C₂₁ H₃₀ Cl₂ N₂ O₂.1/2 H₂ O: C, 59.71;H, 7.40; N, 6.63. Found: C, 59.59; H, 7.48; N, 6.51.

EXAMPLE 901-((N-Methylamino)methyl-N-(2-(3-amino-4-hydroxyphenyl)ethyl))-6-methoxytetralin dihydrochloride

The product from Example 89 was catalytically reduced as in Example 66but replacing 5% Pd/C with 20% pd/C and gave the desired compound, m.p.188°-90° C. Anal. calcd. for C₂₁ H₃₀ Cl₂ N₂ O₂.1/2 H₂ O: C, 59.71; H,7.40; N, 6.63. Found: C, 59.59; H, 7.48; N, 6.51.

EXAMPLE 91 6-Methoxy-1,2,3,4-tetrahydro-1-naphthylene carboxylic acid

A mixture of 1-cyano-6-methoxy-1,2,3,4-tetrahydronaphthalene (18.7 g;0.1 mol), 45% aq. KOH solution (220 ml) and ethylene glycol (180 ml) wasrefluxed for 6h. The reaction mixture was cooled to 0° C. and acidifiedwith cold concentrated hydrochloric acid. The acidic solution wasextracted with methylene chloride. The organic layer was washed withbrine, separated dried (MgSO₄), filtered, and evaporated to afford ca.20 g of an oily residue. Crystallization with ether/hexane afforded ca.17.1 g (83%) of a white crystalline solid, m.p. 81°-82° C.

EXAMPLE 92 N-Methoxy-N-methyl-6-methoxy-1,2,3,4-tetrahydro-1-naphthylenecarboxamide

The product of Example 91 (15 g) was dissolved in benzene (100 ml) andoxalyl chloride (15 ml) and refluxed 1 hr under N₂. The solvent wasevaporated and the residue azeotroped with benzene (2×40 ml). Theresulting acid chloride (18.4 g), and N,O-dimethylhydroxyl aminehydrochloride was dissolved in ethanol free chloroform (200 ml) and thesolution cooled to 0° C., then pyridine (13.4 ml) was slowly added. Themixture was then stirred at room temperature for 1 h then evaporated todryness. The residue was partitioned between brine and a 1:1 mixture ofEt₂ O and CH₂ Cl₂. The organic layer was separated, dried (MgSO₄),filtered, and evaporated affording the desired product as an oil (98%yield).

EXAMPLE 93 1-(1,2,3,4-Tetrahydro-6-methoxy 1-naphthyl)ethan-1-one

The product from example 92 (4.98 g) was dissolved in dry THF (100 ml)cooled to 0° C., then a solution of methylmagnesium Grignard (20 ml of a2.9M ether solution) was added under N₂. The reaction was stirred at 0°C. for 11/2 hr then diluted with ether (100 ml) and poured onto asaturated solution of NH₄ Cl. Methylene chloride was added (100 ml) andthe organic layer separated, washed with brine, dried (MgSO₄), filteredand evaporated affording a viscous oil (95% yield).

EXAMPLE 94 2-(1,2,3,4-Tetrahydro-6-methoxy-1-naphthyl)pyrrolidine

The product from Example 92 (2.49g) was dissolved in dry THF (50 ml) andcooled to 0° C. Then, an excess (3-4 equiv.) of2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane-1-propyl magnesiumbromide was added and the reaction stirred at 0° C. warming to roomtemperature overnight. The reaction was cooled to 0° C. then 10% HCl inEtOH was slowly added, followed by stirring for 3 h at room temperature.The solvent was evaporated and the residue dissolved in methanol. Themixture was cooled to 0° C., then treated with an excess of NaBH₄ andthe mixture stirred at room temperature for 3 h. The solvent wasstripped in vacuo and the residue partitioned between ether and H₂ O.The acidic aqueous layer was made basic then extracted with methylenechloride. The organic extract was dried (MgSO₄), filtered and evaporatedin vacuo and the product purified by column chromatography on silica geleluting with 1:6 EtOH/CH₂ Cl₂ containing NH.sub. 4 OH affording 1.2 g ofdesired product.

EXAMPLE 95N-(2-(2-Furyl)ethyl)-2-(1,2,3,4-tetrahydro-6-methoxy-1-naphthyl)pyrrolidinedifumarate

The product from Example 94 was reacted as described in Examples 18 and19 but replacing 2-thiopheneacetic acid with 2 furylacetic acid and gavethe desired product, m.p. 110 111° C. Anal. calcd. for C₂₉ H₃₇ NO₁₀ : C,62.47; H, 6.33; N, 2.51. Found: C,62.90; H, 6.39; N, 2.55.

EXAMPLE 96N-(2-(2-Thienyl)ethyl)-2-(1,2,3,4-tetrahydro-6-methoxy-1-naphthyl)pyrrolidinemethanesulfonate

The product from Example 94 was reacted as described in Examples 18 and19 and afforded the desired product.

EXAMPLE 97N-(2-(m-Fluorophenyl)ethyl)-2-(1,2,3,4-tetrahydro-6-methoxy-1-naphthyl)pyrrolidine methanesulfonate

Using the product from Example 94 and the procedures of Examples 18 and19, but replacing 2-thienylacetic acid with m-fluorophenylacetic acidgave the desired product.

EXAMPLE 98 1-(6-Methoxy-1 2,3,4-tetrahydro-1-naphthyl)-N-ethyl-1-aminoethane

The product of Example 93(2g) was dissolved in anhydrous MeOH (20 ml)and EtNH2-(3 ml) and the pH adjusted to ca. 8 with methanolic HCl.Sodium cyanoborohydride (500 mg) was added and an additional 2 mlmethanolic HCl dropwise. The reaction was stirred under N₂ for 48 h then6-N-HCl added to pH<2. The methanol was removed under vacuum and theaqueous layer extracted with CH₂ Cl₂ (2×100 ml). The organic layer wasseparated, washed with brine, dried (MgSO₄), filtered and evaporatedgiving 0.18 g of an oil. The neutral CH₂ Cl₂ extract was dried (MgSO₄),filtered and evaporated then partitioned between 2-N-HCl and a mixtureof ether/hexane. The organic layer was separated and discarded. Theacidic layer was basified and extracted with CH₂ Cl₂. The organic layerwas separated, dried (MgSO₄), filtered and evaporated giving anadditional 1.12 g of product.

EXAMPLE 99 1-(6-Methoxy-1,2,3,4-tetrahydro-1-naphthyl)-N-methyl-1-aminoethane

Using the procedure described in Example 98 but replacing EtNH₂ withmethylamine afforded the desired product in 59% yield.

EXAMPLE 100N-(2-Phenylethyl)-1-(6-methoxy-1,2,3,4-tetrahydro-1-naphthyl)-N-methyl-1-aminoethane hydrochloride

Using the procedures described in Examples 4 and 5 but replacing the2-thiopheneacetic acid with phenylacetic acid and the product fromExample 99 gave the desired compound, m.p. 159°-160° C. Anal. calcd. forC₂₂ H₃₀ C1NO: C, 73.23; H, 8.32; N. 3.88. Found: C, 73.28; H, 8.28; N.3.86.

EXAMPLE 101N-(2-(Phenyl)ethyl)-1-(6-hydroxy-1,2,3,4-tetrahydro-1-naphthyl)-N-methyl-1-aminoethane hydrobromide

Using the product from Example 100 and the procedure of Example 9 gavethe desired product, m.p. 88°-90° C. Anal. calcd. for C₂₁ H₂₈ BrNO: C,64.62; H, 7.18; N, 3.59. Found: C, 64.50; H, 7.14; N, 3.54.

EXAMPLE 102N-(2-(2-Furyl)ethyl)-1-(6-methoxy-1,2,3,4-tetrahydro-1-naphthyl)-N-methyl-1-aminoethane methanesulfonate

Using the product from Example 99 and the procedures described inExamples 18 and 19 but replacing 2-thiopheneacetic acid with 2furylacetic acid gave the desired product, (M⁺ H)₊ 314.

EXAMPLE 103N-(2-(2-Thienyl)ethyl)-1-(6-methoxy-1,2,3,4-tetrahydro-1-naphthyl)-N-methyl-1-aminoethane hydrochloride

Using the product from Example 99 and the procedures described inExamples 4 and 5 gave the desired product, m.p. 160°-61° C. Anal. calcd.for C₂₀ H₂₈ C1NOS: C, 65.66; H, 7.66; N, 3.83. Found: C, 65.82; H, 7.74;N, 3.82.

EXAMPLE 104N-(2-(2-Furyl)ethyl)-1-(6-methoxy-1,2,3,4-tetrahydro-1-naphthyl)-N-ethyl-1-aminoethane hydrochloride

Using the compound from Example 98 and the procedures described inExamples 18 and 19 but replacing 2-thiopheneacetic acid with2-furylacetic acid gave the desired product, (M⁺ H)₊ 328. ¹ H NMR(CDCl₃): 0.85(3H,d, J=8.0 Hz), 1.04 (3H, t, J=8.0 Hz), 1.32-1.47 (1H,m),1.61 1.72 (1H,m), 1.75-1.88 (1H,m), 2.26-2.43 (2H,m), 2.5-2.92 (9H,m),3.75 (3H,s), 6.1 (1H,dd,J=3.0, 0.6 Hz), 6.28 (1H,dd,J=3.0, 1.5 Hz), 6.61(1H,d,J=3.0 Hz), 6.63 (1H,dd,J=9.0, 3.0 Hz), 7.0 (1H,d,J=8.0 Hz), 7.3(1H,dd,J=1.5, 0.6 Hz).

EXAMPLE 105 1-(1,2,3,4-Tetrahydro-6-methoxy-1-naphthyl)propan-1-one

Using the product of Example 92 and the procedure of Example 93 butreplacing methyl magnesium bromide with ethyl magnesium bromide gave thedesired product.

EXAMPLE 106 1-(6-Methoxy-1,2,3,4-tetrahydro-1-naphthyl)-N-methyl-1-aminopropane

Using the product of Example 105 with the procedure described in Example98 but replacing the ethylamine with methylamine gave the desiredproduct.

EXAMPLE 107N-(2-(2-Furyl)ethyl)-1-(6-methoxy-1,2,3,4-tetrahydro-1-naphthyl)-N-methyl-1-aminopropane hydrochloride

Using the product from Example 106 and following the proceduresdescribed in Examples 18 and 19 but replacing 2-thiopheneacetic acidwith 2 furylacetic acid gave the desired product. ¹ H NMR (CDCl₃): 0.84-1.0 (5H,m); 1.4-1.9 (3H,m); 2.38 (3H,s); 2.5-2.95 (9H,m); 3.65 (3H,s);6.1 (1H,dd,J=3.0, 0.6 Hz); 6.29 (1H,dd,J=3.0, 1.5 Hz); 6.59 (1H, d,J=3.0Hz); 6.63 (1H,dd,J=9.0, 3.0 Hz); 6.90 (1H,d,J=9.0); 7.28 (1H,dd,J=1.5,0.6 Hz).

EXAMPLE 108N-(2-(m-Fluorophenyl)ethyl)-1-(6-methoxy-1,2,3,4-tetrahydro-1-naphthyl)-N-methyl-1-aminopropane hydrochloride

Using the product of Example 106 and the procedures described inExamples 4 and 5 but replacing 2-thiopheneacetic acid withm-fluorophenylacetic acid gave the desired product.

EXAMPLE 109 N-(2-(m-Fluorophenyl)ethyl)-1-(6-hydroxy-1,2,3,4-tetrahydro1-naphthyl)-N-methyl-1-amino propane hydrobromide

Using the product of Example 108 with the procedure of Example 9 gavethe desired product.

EXAMPLE 110N-(2-(m-Fluorophenyl)ethyl)-2-(1,2,3,4-tetrahydro-1-naphthyl-6-hydroxy)pyrrolidine hydrobromide

Using the product from Example 97 and the procedure of Example 9 gavethe desired product.

EXAMPLE 111 1-(N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-5-hydroxytetralin hydrochloride

1-(N-methylamino)methyl-5-trimethylsilyoxy tetralin was reacted as inExample 18 and gave the desired amide. This amide was then treated as inExample 5 and afforded the desired compound, m.p. 202°-3° C. (freebase).

EXAMPLE 112 6-Acetamido-3,4-dihydronaphthylene-1-carbonitrile

Using the procedure of Example 1, but replacing 6-methoxy 1 tetralonewith 6 acetamido-1-tetralone gave the desired product.

EXAMPLE 113 6-Amino-(1,2,3,4-tetrahydro-1-naphthylene) carboxylic acid

The product from Example 112 was reduced with NaBH₄ in MeOH and DME thenhydrolyzed to the carboxylic acid as described in Example 92.

EXAMPLE 114 1-((N-Methylaminomethyl-N-(2-phenylethyl))-6-amino tetralindihydrochloride

Replacing 2-thiopheneacetic acid with the product from Example 113 andusing the procedure of Example 18 with-N-methylphenethyl amine gave thedesired amide. This amide was reduced as in Example 19 and gave thedesired product, m.p. 255°-56° C. Anal. calcd. for C₂₀ H₂₈ Cl₂ N₂ : C,72.59; H, 8.22; N. 8.46. Found: C, 72.42; H, 8.41; H, 8.39.

EXAMPLE 1151-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-5-iodo-6-hydroxytetralin hydrochloride

The product from Example 7 (free base) was iodinated with silvertrifluoroacetate in CH₂ Cl₂ at 0° C., and afforded the desired compound.

EXAMPLE 116 1-((N-Methylamino)methyl-N-(2-phenylethyl))-5-iodo-6-hydroxytetralin hydrochloride

The product from Example 11 (free base) was iodinated with chloramine Tand sodium iodide then treated with methanolic HCl to give the product,m.p. 112°-114° C.

EXAMPLE 117 1-((N-Methylamino)methyl-N-(2-phenylethyl))-5-iodo-6-aminotetralin dihydrochloride

The product from Example 114 was reacted as described in the procedureof Example 116 and afforded the desired product.

EXAMPLE 118 1-((N-Methylamino)methyl-N-(3-(2-furyl)propyl))-6-methoxytetralin hydrochloride

The product from Example 3 was reacted with 2-furylpropionic acid usingthe procedure of Example 18. The resulting amide was reduced asdescribed in Example 19 and afforded the desired compound, m.p. 140°-41°C. Anal calcd. for C₂₀ H₂₈ C1NO₂ : C, 66.33; H, 7.21; N, 4.55. Found: C,66.27; H, 7.19; N, 4.53.

EXAMPLE 119 1-((N-Methylamino)methyl-N(2-(m-methylphenyl)-ethyl))-5-methoxy indane hydrochloride

Using the procedures described in Examples 1-5 but replacing 6 methoxy 1tetralone with 5-methoxy-1-indanone and replacing 2-thiopheneacetic acidwith m methylphenyl acetic acid gave the desired compound, m.p. 183°-84°C. Anal. calcd. for C₂₁ H₂₈ C1NO.H₂ O: C, 69.31; H, 8.31; N, 3.85.Found: C, 69.44; H, 7.93; N, 3.90.

EXAMPLE 120 6-Methoxy-1-(3-phenylpyrrolidino-1-carbonyl) tetralin

Using 3-phenylpyrrolidine and the procedure described in Example 4 butreplacing 2-thiopheneacetic acid with the product of example 91 gave thedesired amide.

EXAMPLE 121 6-Methoxy-1-(3-phenylpyrrolidino-1-methyl) tetralinhydrochloride

Reduction of the product of Example 120 using the procedure described inExample 17 gave the desired compound, m.p. 228°-232° C. Anal. calcd. forC₂₂ H₂₈ C1NO: C, 73.83; H, 7.89; N, 3.91. Found: C, 73.68; H, 7.86; N,3.91.

EXAMPLE 122 2-(2-Thienylmethyl)pyrrolidine

Using the procedure of Example 92 but replacing the product of Example91 with 2-thiopheneacetic acid gave a 90% yield of the desiredcarboxamide. This carboxamide was reacted as described in Example 94 andgave the desired product in 43% yield.

EXAMPLE 123 6-Methoxy-1-(2-(2-thienylmethyl)pyrrolidino-1-methyl)tetralin hydrochloride

The product of Example 122 was reacted as described in Example 4 butreplacing 2-thiopheneacetic acid with the product of Example 91 gave thedesired amide. This was reduced as described in Example 17 and affordeda foam, m.p. 85°-89° C. Anal. calcd. for C₂₁ H₂₈ C1NOS.1/2 H₂ O: C,65.18; H, 7.55; N. 3.62. Found: C, 65.06; H, 7.21; N, 3.82.

EXAMPLE 124 5-Methoxy-3-phenyl-1-tetralone

o-Anisaldehyde (20.5 g) was treated with 1,3-propanedithiol (24 ml) inthe presence of BF₃ etherate (4 ml) and CH₂ Cl₂ (300 ml). This dithianederivative (4.7 g) was reacted with n-BuLi (2.5 M hexane solution) (7.3ml), methyl cinnamate (3.4 g) and 1,3-dimethyl-2-imidazolidone-(4.6 ml)affording the desired product (M+H)⁺ 389. Desulfurization wasaccomplished with Raney Nickel and EtOH, followed by hydrolysis to thedesired carboxylic acid. Cyclization to the desired 5 methoxy 3 phenyl 1tetralone was accomplished by heating with polyphosphoric acid, (M+H)⁺253.

EXAMPLE 1251-(N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-3-phenyl-5-methoxytetralin hydrochloride

The product from Example 124 was reacted as described in Examples 1-5and gave the desired product, (M+H)⁺ 392.

EXAMPLE 126 6-Methoxy-3-phenyl-1-tetralone

Using the procedure described in Example 124 but replacingo-anisaldehyde with m-anisaldehyde afforded the desired product, (M+H)⁺253.

EXAMPLE 1271-(N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-3-phenyl-6-methoxytetralin hydrochloride

The product from Example 126 was treated as described in Examples 1-5and afforded the desired product, m.p. 155°-160° C. Anal. calcd. for C₂₅H₃₀ NOS: C, 70.15; H, 7.06; N. 3.27. Found: C, 70.42; H, 7.19; N, 3.24.

EXAMPLE 1281-((N-Methylamino)methyl-N-(2-(2-furyl)ethyl))-methoxy-7-methyl tetralinhydrochloride

Using the procedures described in Examples 1-3 and Examples 18-19 butreplacing 6 methoxy 1-tetralone with the product of Example 38 andreplacing 2-thiopheneacetic acid with 2-furylacetic acid gave thedesired compound, m.p. 188°-89C. Anal. calcd. for C₂₀ H₂₈ C1NO₂ : C,68.65; H, 8.07; N, 4.00. Found: C, 68.59; H, 8.20; N, 3.95.

EXAMPLE 129 1-((N-Methylamino)methyl-N-(2-(2-thieny)ethyl))-5-chlorotetralin hydrochloride

Using the procedures described in Examples 46-49 but replacing6-chloro-1-tetralone with 5-chloro-1-tetralone afforded the desiredproduct, m.p. 216°-217° C. Anal. calcd. for C₁₈ H₂₃ Cl₂ NS: C, 60.67; H,6.18; N, 3.93. Found: C, 60.67; H, 5.57; N, 3.95.

EXAMPLE 130 6-Methoxy-3-methyl-1-tetralone

The compound was prepared as described in Example 124 replacing methylcinnamate with ethyl crotonate affording the desired product, (M+H)⁺191.

EXAMPLE 131 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-3-methyl-6-methoxy tetralin hydrochloride

Using the procedures described in Examples 1-5 but replacing6-methoxy-1-tetralone with the product of Example 130 gave the desiredcompound, (M+H)⁺ 330.

EXAMPLE 132 Dimethyl (2-thienyl)methylidene malonate

A solution of 2-thiophene carboxaldehyde (20.0 g), dimethyl malonate(22.1 ml), acetic acid (2.0 ml) and piperidine (0.7 ml) in 130 ml ofbenzene was heated at reflux under azeotropic conditions. After 4 hoursthe reaction mixture was cooled to room temperature, diluted with Et₂ O(100 ml), washed with 5% HCl (50 ml), brine (50 ml), sat. NaHCO₃ (50ml), dried (MgSO₄), filtered and concentrated in vacuo. Distillation ofthe resulting amber oil under reduced pressure afforded 39 g of thedesired compound which crystallized upon standing, m.p. 44°-46° C.

EXAMPLE 133 3-Cyano-3-(2-thienyl) propionic acid

To a mechanically stirred solution of 12.4 g of Example 132 in 135 ml ofabs. EtOH was added in one portion a solution of KCN (3.9 g) in 7.0 mlof water, and the mixture heated to 70° C. After 20 hr at 70° C., thereaction mixture was cooled to 15° C., filtered, and concentrated invacuo. The residue was taken up into Et₂ O (150 ml) and 10% aq. K0H (100ml). The layers were separated and the aqueous phase reextracted withEt₂ O (100 ml).

The organic extracts were combined, dried (MgSO₄), filtered andconcentrated to afford an amber liquid. Bulb to bulb distillation underreduced pressure afforded 7.89 g of a pale yellow liquid which wascarried on to the next reaction without further purification.

EXAMPLE 134 4-(2-Thienyl)-2-pyrrolidinone

To a suspension of 1.23 g of cobalt boride and 2.0 g of the product ofExample 133 in 60 ml of absolute methanol was added 2.50 g of boranetert-butyl amine complex, and the reaction was heated to reflux. After 6h at reflux, the reaction was cooled to room temperature, filtered andconcentrated. The residue was taken up unto EtOAc (70 ml) and 5% aqueousHCl (25 ml). The phases were separated and the aqueous phase reextractedwith EtOAc (50 ml). The extracts were combined, dried (MgSO₄), filteredand concentrated. Chromatography of the residue on silica gel (elutionwith EtOAc) afforded 0.775 g of product as a white, crystallinematerial, m.p. 75.0°-76.5° C. Anal. calcd. for C₈ H₉ NOS: C, 57.46; H,5.42; N, 8.38. Found: C, 57.64; H, 5.58; N, 8.47.

EXAMPLE 135 3-(2-Thienyl)pyrrolidine

To a suspension of LiA1H₄ (0.46 g) in THF (25 ml) was added the productof Example 134 (1.0 g) in THF (30 ml). After the addition was completethe reaction was heated at reflux for 4 hrs.

The reaction was cooled to 0° C. and quenched by the dropwise additionof water (0.46 ml), 15% aq. KOH (0.46 ml), followed by another 1.4 ml ofwater. After 30 min., the reaction was filtered and concentrated. Theresidue was taken up into EtOAc (60 ml), washed thoroughly with 5% aq.HCl (2×30 ml). The aqueous phases were combined, basified with 15% aq.KOH to pH 10 and extracted with EtOAc (2×50 ml). The organic extractswere combined, dried (MgSO₄), filtered and concentrated. Bulb to bulbdistillation under reduced pressure afforded the desired product, (M+H)⁺154.

EXAMPLE 136 6-Methoxy-1-(3-(2-thienyl)pyrrolidino-1-methyl) tetralinhydrochloride

Using the products of Examples 91 and 135 and the procedures describedin Examples 4 and 17, the desired compound was afforded, 114°-117° C.dec. Anal. calcd. for C₂₀ H₂₆ C1NOS: C, 66.00; H, 7.20; N, 3.85. Found:C, 65.68; H, 7.14; N, 3.79.

EXAMPLE 137 N-(2-(2-furyl)ethyl)2-(1,2,3,4-tetrahydro-6-hydroxy-1-naphthyl) pyrrolidine hydrobromide

The product of Example 95 was reacted as described in Example 9 and gavethe desired compound.

EXAMPLE 138 N-(2-(2-Furyl)ethyl)2-(1,2,3,4-tetrahydro-6-methoxy-3-methyl-1-naphthyl) pyrrolidinehydrochloride

The product from Example 133 was reacted as described in Example 13 andthen Examples 91 and 92. This product was treated as in Example 94 andthen Examples 18 and 19, affording the desired compound.

EXAMPLE 139N-(2-(2-Furyl)ethyl)-2-(1,2,3,4-tetrahydro-6-hydroxy-3-methyl-1-naphthyl)pyrrolidine hydrobromide

The product of Example 138 was reacted as in Example 9 giving thecompound.

EXAMPLE 140N-(2-(2-Furyl)ethyl)-2-(1,2,3,4-tetrahydro-6-methoxy-3-phenyl-1-naphthyl)pyrrolidine hydrochloride

The product of Example 126 was reacted as described in Example 13 andthen Examples 91 and 92. This product was used as described in Example94, followed by Examples 18 and 19, giving the desired compound.

EXAMPLE 1411-((N-methylamino)methyl-N-(2-(2-furyl)ethyl))-6-methoxy-7-fluorotetralin methanesulfonate

Using the procedures described in Example 1 but replacing6-methoxy-1-tetralone and Zn1₂ with 6-methoxy-7-fluoro tetralone andLiCN afforded the 1-cyano derivative. Catalytic reduction with Pd/C at 4atm. gave the corresponding 1 aminomethyl tetralin derivative in 97%yield. Utilizing this product and the procedures in examples 16-19 gavethe desired product, m.p. 115°-116° C. Anal. calcd. for C₁₉ H₂₄ NO₂F.CH₃ SO₃ H: C, 58.09; H,6.82; N, 3.39. Found: C, 57.86; H, 6.84; N,3.43.

EXAMPLE 142 1,2,3,4-Tetrahydro-5,6-methylenedioxy-1-naphthylenecarboxylic acid

To a solution of 1-cyano-3,4-dihydro-5,6-methylenedioxynaphthylene (5.0g) in ethanol (80 ml) was added in small portions sodium borohydride(1.44 g). After the addition was complete the reaction was heated toreflux. After 2 hours, the reaction was cooled and concentrated. Theresidue was taken up into 1-N-HCl and CH₂ Cl₂ and the layers separated.The organic phase was washed with water, brine, dried over MgSO₄,filtered and concentrated. The resulting material was dissolved intoethylene glycol(41 ml) treated with 45% KOH (30 ml) and heated toreflux. After 3 hours the reaction was cooled with an ice bath, dilutedwith ice/water and acidified with concentrated HCl, upon which a whiteprecipitate formed. The product was extracted with ethyl acetate (3×75ml), washed with brine, dried over MgSO₄, filtered and concentrated toafford the desired product, m.p. 165°-167° C.

EXAMPLE 143a 5,6-Methylenedioxy-1-(3-phenylpyrrolidino-1-methyl)tetralin methanesulfonate

Using 3-phenylpyrrolidine and the procedures described in Examples 4 and5 but replacing 2-thiopheneacetic acid with Example 142 afforded thedesired compound, m.p. 123°-124° C. Anal calcd. for C₂₂ H₂₅ NO₂.CH₃ SO₃H: C, 64.01; H, 6.77; N. 3.25. Found: C, 63.97; H. 6.83; N. 3.22.

EXAMPLES 143b, 143c5,6-Methylenedioxy-1R-(3R-phenylpyrrolidino-1-methyl) tetralinmethanesulfonate and 5,6-Methylenedioxy 1R (3S phenylpyrrolidino 1methyl) tetralin methanesulfonate

The product of Example 143a was chromatographed on silica gel (elutionwith 20% ET₂ O /hexanes, saturated with NH₃) to provide the R,R/S,Sdiastereomer which was converted to the corresponding methane sulfonatederivative, m.p. 166°-168° C. Anal. calcd. for C₂₂ H₂₅ NO₂. CH₃ SO₃ H:C, 64.01; H, 6.77; N, 3.24. Found: C, 63.89; H, 6.74; N, 3.24. Furtherelution provided the R,S/S,R diastereomer which was converted to thecorresponding methane sulfonate derivative, m.p. 161°-162° C. Anal.calcd. for C₂₂ H₂₅ NO₂. CH₃ SO₃ H: C, 64.01; H, 6.77; N, 3.24. Found: C,63.84; H, 6.68; N, 3.21.

EXAMPLE 144 5,6-Methylenedioxy-1-(3-(2-thienyl)pyrrolidino-1-methyl)tetralin methanesulfonate

Using Example 135 and the procedures described in Examples 4 and 5 butreplacing 2-thiopheneacetic acid with Example 142 afforded the desiredcompound, m.p. 150°-151° C. Anal. calcd. for C₂₀ H₂₃ NO₂ S.CH₃ SO₃ H: C,57.64; H, 6.22; N, 3.20. Found: C, 57.17; H, 6.16; N, 3.15.

EXAMPLE 145 1,2,3,4-Tetrahydro-5-methoxy-1-naphthylene carboxylic acid

Using the procedure described in Example 142 but replacing1-cyano-3,4-dihydro-5,6-methylenedioxynaphthylene with1-cyano-3,4-dihydro-5-methoxynaphthylene provided the desired product,m.p. 101°-102° C.

EXAMPLE 146 5-Methoxy-1-(3-(2-thienyl)pyrrolidino-1-methyl) tetralinhydrochloride

Using Example 135 and the procedures described in Examples 4 and 5 butreplacing 2-thiopheneacetic acid with Example 145 afforded the desiredcompound, m.p. >230° C. Anal calcd. for C₂₀ H₂₅ NOS HCl: C. 66.00; H,7.20; N, 3.85. Found: C, 65.87; H, 7.19; N, 3.83.

EXAMPLE 147 6-Fluoro-1,2,3,4-tetrahydro-1-naphthylene carboxylic acid

Using the procedure described in Example 142 but replacing1-cyano-3,4-dihydro-5,6-methylenedioxynaphthylene with1-cyano-6-fluoro-3,4-dihydronaphthylene provided the desired product,m.p. 90°-91° C.

EXAMPLE 148 6-Fluoro-1-(3-phenylpyrrolidino-1-methyl) tetralinmethanesulfonate

Using 3-phenylpyrrolidine and the procedures described in Examples 4 and5 but replacing 2-thiopheneacetic acid with Example 147 afforded thedesired compound, m.p. 166°-167° C. Anal. calcd. for C₂₁ H₂₄ FN.CH₃ SO₃H: C, 65.16; H, 6.96; N, 3.45. Found: C, 64.98; H, 6.93; N, 3.42.

EXAMPLE 149 6-Fluoro-1-(3-(2-thienyl)pyrrolidino-1-methyl) tetralinmethanesulfonate

Using Example 135 and the procedures described in Examples 4 and 5 butreplacing 2-thiopheneacetic acid with Example 147 afforded the desiredcompound, m.p. 136°-137° C. Anal. calcd. for C₁₉ H₂₄ FN.CH₃ SO₃ H: C.58.37; H, 6.37; N. 3.40. Found: C, 58.22; H, 6.34; N, 3.35.

EXAMPLE 150 2,3-Dihydro-4-methoxy-1-indene carboxylic acid

Using the procedure described in Example 142 but replacing1-cyano-3,4-dihydro-5,6-methylenedioxynaphthylene with1-cyano-2,3-dihydro-5-methoxy-1-indene provided the desired product,m.p. 117°-118° C.

EXAMPLE 151 5-Methoxy-1-(3-(2-thienyl)pyrrolidino-1-methyl) indanehydrochloride

Using Example 135 and the procedures described in Examples 4 and 5 butreplacing 2-thiopheneacetic acid with Example 150 provided the desiredcompound, m.p. 202°-204° C. dec. Anal. calcd. for C₁₉ H₂₃ NOS.HCl: C,65.22; H, 6.91; N, 4.00. Found: C, 65.04; H, 6.92; N, 3.93.

EXAMPLE 152 5-Methoxy-1-(3-phenylpyrrolidino-1-methyl) indanehydrochloride

Using 3-phenylpyrrolidine and the procedures described in Examples 4 andbut replacing 2-thiopheneacetic acid with Example 150 provided thedesired compound, m.p. 126°-130° C. dec. Anal. calcd. for C₂₂ H₂₅ NO.CH₃SO₃ H: C, 65.48; H, 7.24; N, 3.47. Found: C, 65.44; H, 7.31; N. 3.46.

EXAMPLE 153 5-Methoxy-1-(3-(m-fluorophenyl)pyrrolidino-1-methyl) indanehydrochloride

Using 3-(m-fluorophenyl)pyrrolidine and the procedures described inExamples 4 and 5 but replacing 2-thiopheneacetic acid with Example 150provided the desired compound, m.p. 205°-207° C. dec. Anal. calcd. forC₂₁ H₂₄ FNO.HCl: C, 69.70; H, 6.96; N, 3.87. Found: C, 69.54; H, 7.06;N, 3.83.

EXAMPLE 154 6-Amino-1,2,3,4-tetrahydro-1-naphthylene carboxylic acidhydrochloride

Using the procedure outlined in Example 1 but replacing 6 methoxy1-tetralone with 6-acetamido 1 tetralone afforded the desiredunsaturated nitrile. A suspension of the above nitrile (24 g) in 260 mLof a 1:1 mixture of ethanol and dimethoxyethyl ether was treated withsmall portions of sodium borohydride (15 g). After the addition wascomplete the reaction was heated at reflux for 20 hours. The reactionwas cooled to room temperature, quenched by the dropwise addition ofacetone and concentrated. The residue was taken up into saturated NH₄ Cland CH₂ Cl₂. The phases were separated and the aqueous phase reextractedwith CH₂ Cl₂. The organic extracts were combined, dried over magnesiumsulfate, filtered and concentrated to provide the desired saturatednitrile.

The above nitrile was taken up into concentrated hydrochloric acid (160ml) and heated at reflux for 5 hours. The reaction was cooled to 0° C.and the resulting precipitate collected and washed with a 10%ethanol/ether solution to provide the desired product.

EXAMPLE 1551-((6-amino-1,2,3,4-tetrahydro-1-naphthalenyl)carbonyl)-3-phenylpyrrolidine

A mixture of Example 154 (2.3 g) and thionyl chloride (50 ml) wereheated at reflux for 45 minutes. The reaction was concentrated and theresidue was co-concentrated with toluene (3×50 ml). To a solution of3-phenylpyrrolidine in CH₂ Cl₂ (30 ml) containing triethylamine (4.2 ml)at 0° C., was added dropwise a solution of the above acid chloride inCH₂ Cl₂ (30 ml). After 8 hours, the reaction was concentrated to afforda brown oil. The residue was taken up into a mixture of water and ethylacetate. The layers were separated and the organic phase washed with 1 NNaOH, brine, dried over magnesium sulfate, filtered and concentrated.Chromatography (elution with 2% CH₃ OH/CH₂ Cl₂) on silica gel provided2.7 g of the desired product.

EXAMPLE 156 6-Amino-1-(3-phenylpyrrolidino-1-methyl) tetralindihydrochloride

Using the procedure described in Example 19 but replacing Example 18with Example 155 yielded the desired compound, m.p. >260° C. Anal.calcd. for C₂₁ H₂₆ N₂.HCl: C, 66.49; H, 7.44; N, 7.38. Found: C, 65 81;H, 7.41; N. 7.21.

EXAMPLE 157 6-(N-methylamino)-1-(3-phenylpyrrolidino-1-methyl) tetralindihydrochloride

Using the procedure outlined in Example 3 but replacing Example 2 withExample 155 provided the desired compound, m.p. 231° C. Anal. calcd. forC₂₂ H₂₈ N₂.2HCl: C, 67.17; H, 7.69; N, 7.12. Found: C, 66.97; H, 7.88;N,. 7.12.

EXAMPLE 158 8-fluoro-5,6, methylenedioxy-1-tetralone

To a solution of 8-fluoro-5,6-dimethoxy-1-tetralone (3.0 g) in toluene(30 ml) was added in small portions aluminum chloride (9.0 g). After theaddition was complete, the reaction was heated to 80° C. and after 30min. cooled to room temperature. The reaction mixture was poured intoconcentrated HCl/ice and the product extracted with ethyl acetate. Theorganic layer was washed with 1 N HCl, brine, dried over MgSO₄, filteredand concentrated to afford 2.0 g of product. To a mechanically stirredsuspension of this material in1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)pyrimidinone (14 ml) was addedcesium carbonate (4.7 g) followed by the addition of bromochloromethane(0.99 ml) and the resulting mixture heated to 70° C. with vigorousstirring. After 4.5 hours, the reaction was cooled and poured into water(50 ml). The product was extracted with ethyl acetate (2×50 ml) and theextracts were combined, dried over MgSO₄, filtered and concentrated.Chromatography of the residue on silica gel (elution with 25%EtOAc/hexanes) afforded the desired product, m.p. 174°-175° C. Anal.calcd. for C₁₁ H₉ FO₃ : C, 63.46; H, 4.36. Found: C, 63.28; H, 4.42.

EXAMPLE 159 8-Fluoro-1,2,3,4-tetrahydro-5,6-methylenedioxy-2-naphthylenecarboxylic acid

Using the procedure in Example 1, but replacing 6-methoxy-1-tetralonewith Example 158 afforded the unsaturated nitrile. m.p. 140.5°-142.5° C.Anal. calcd. for C₁₂ H₈ FNO₂ : C, 66.36; H, 3.71; N, 6.45. Found: C,66.17; H, 3.81; N, 6.34. This material was subjected to the reactionconditions described in Example 142 to provide the desired material.

EXAMPLE 160 8-Fluoro-5,6-methylenedioxy-1-(3-phenylpyrrolidino-1-methyl)tetralin hydrochloride

Using 3-phenylpyrrolidine and the procedures described in Example 4 and5 but replacing 2-thiopheneacetic acid with Example 159 afforded thedesired compound. m.p. 169°-170° C. Anal. calcd. for C₂₂ H₂₄ NO₂. CH₃SO₃ H: C, 61.45; H, 6.28; N, 3.12. Found: C, 61.52; H, 6.25; N, 2.99.

EXAMPLE 161 8-Fluoro-5,6-methylenedioxy-1-(3-(m-fluorophenyl)pyrrolidino-1-methyl) tetralin hydrochloride

Using 3-(m-fluorophenyl)pyrrolidine and the procedures described inExample 4 and 5 but replacing 2-thiopheneacetic acid with Example 159afforded the desired compound.

EXAMPLE 1628-Fluoro-5,6-methylenedioxy-1-(3-(2-thienyl)pyrrolidino-1-methyl)tetralin hydrochloride

Using Example 135 and the procedures described in Example 4 and 5 butreplacing 2-thiopheneacetic acid with Example 159 afforded the desiredcompound.

EXAMPLE 1635,6-Methylenedioxy-1-(3-(m-fluorophenyl)pyrrolidino-1-methyl) tetralinmethanesulfonate

Using 3-(m-fluorophenyl)pyrrolidine and the procedures described inExample 4 and 5 but replacing 2-thiopheneacetic acid with Example 142afforded the desired compound, m.p. 177°-179° C. dec. Anal. calcd. forC₂₂ H₂₄ FNO₂. CH₃ SO₃ H: C, 61.45; H, 6.28; N, 3.12. Found: C, 61.27; H,6.32; N, 3.07.

EXAMPLE 1641-(N-Ethylamino)methyl-N-(2-(2-thienyl)ethyl))-5,6-methylenedioxytetralin hydrochloride

The desired compound (m.p. 163°-164° C.) was prepared using theprocedures outlined in examples 1, 2, 15, 4 and 5, but replacing6-methoxy-1-tetralone with 5,6-methylenedioxy-1-tetralone. Anal. calcd.for C₂₀ H₂₅ NO₂ S.HCl: C, 63.23; H, 6.90; N. 3.69. Found: C, 63.15; H,6.86; N, 3.64.

EXAMPLE 1651-((N-Ethylamino)methyl-N-(2-m-fluorophenethyl))-5,6-methylenedioxytetralin hydrochloride

The desired compound (m.p. 131.5°-132.5° C.) was prepared using theprocedures in Example 165, but replacing 2-thiopheneacetic acid withm-fluorophenylacetic acid. Anal calcd. for C₂₂ H₂₆ FNO₂.HCl: C, 67.42;H, 6.94; N, 3.57. Found: C, 67.40; H, 6.98; N, 3.51.

EXAMPLE 1661-((N-Methylamino)methyl-N-(2-m-fluorophenethyl))-5,6-methylenedioxytetralin methanesulfonate

Using the procedures in Example 23, but replacing 2-thiopheneacetic acidwith m-fluoroacetic acid provided the desired product upon formation ofthe methanesulfonate salt, m.p. 144°-147° C. Anal. calcd. for C₂₁ H₂₄FNO₂.CH₃ SO₃ H: C, 60.39; H, 6.45; N, 3.20. Found: C, 60.39; H. 6.48; N.3.23.

EXAMPLE 1671-((N-Methylamino)methyl-N-(2-m-fluorophenethyl))-5,6-ethylenedioxytetralin methanesulfonate

The product was prepared (m.p. 174°-175° C.) using the procedures inExample 30, but replacing 2-thiopheneacetic acid withm-fluorophenylacetic acid and formation of the methanesulfonate salt.Anal. calcd. for C₂₂ H₂₆ FNO₂.CH₃ SO₃ H: C, 61.18; H. 6.70; N, 3.10.Found: C, 60.94; H, 6.71; N, 3.09.

EXAMPLE 1681-((N-Ethylamino)methyl-N-(2-(2-thienyl)ethyl))-5,6-ethylenedioxytetralin hydrochloride

Using the procedures outlined in Example 164, but replacing5,6-methylenedioxy-1-tetralone with 5,6-ethylenedioxy-1-tetraloneprovided the desired product. Anal. calcd. for C₂₁ H₂₇ NO₂ S.HCl.1/2H₂O: C, 62.59; H. 7.25; N. 3.48. Found: C, 62.50; H, 6.95; N, 3.55.

EXAMPLE 169 1,2,3,4-Tetrahydro-5,6-ethylenedioxy-1-naphthylenecarboxylic acid

Using the procedure in Example 142 but replacing1-cyano-3,4-dihydro-5,6-methylenedioxy-naphthylene with1-cyano-3,4-dihydro-5,6-ethylene-dioxynaphthylene provided the desiredmaterial.

EXAMPLE 170 5,6-Ethylenedioxy-1-(3-phenylpyrrolidino-1-methyl) tetralinhydrochloride

Using 3-phenylpyrrolidine and the procedures described in Examples 4 and5 but replacing 2-thiopheneacetic acid with Example 169 afforded thedesired compound.

EXAMPLE 171 5,6-Ethylenedioxy-1-(3-(m-fluorophenyl)pyrrolidino-1-methyl)tetralin hydrochloride

Using 3 (m-fluorophenyl)pyrrolidine and the procedures described inExamples 4 and 5 but replacing 2-thiopheneacetic acid with Example 169afforded the desired compound.

EXAMPLE 172 5,6-Ethylenedioxy-1-(3-(2-thienyl)pyrrolidino-1-methyl)tetralin hydrochloride

Using 3-(2-thienyl)pyrrolidine and the procedures described in Examples4 and 5 but replacing 2-thiopheneacetic acid with Example 169 affordedthe desired compound.

EXAMPLE 173a & b(+)-5,6-Methylenedioxy-1R*-(3R*-phenylpyrrolidino-1-methyl) tetralinmethanesulfonate and(-)-5,6-Methylenedioxy-1S*-(3R*-phenylpyrrolidino-1-methyl) tetralinhydrochloride

Using (-)-3R*-phenylpyrrolidine and the procedures described in Examples4 and 5 but replacing 2-thiopheneacetic acid with the product of Example142 afforded a mixture of enantiomerically pure diastereomers.Chromatography on silica gel (elution with 20 % Et₂ O/ Hexanes,saturated with NH₃) provided Example 173a (R,R) after conversion to thecorresponding methane sulfonate salt, [α]_(D) +29.73° (c 0.555, CH₃ OH);[α]_(D) +37.59° (c 0.580, H₂ O). Anal. calcd. for C₂₂ H₂₅ NO₂.CH₃ SO₃ H:C, 64.01; H, 6.77; N, 3.24. Found: C, 63.96; H, 6.79; N, 3.25. Furtherelution provided Example 173b (R,S) which was converted to thecorresponding hydrochloride salt, [α]_(D) -19.07° (c 0.535, CH₃ OH).Overlapping fractions were resubmitted under the above conditions forrechromatography.

EXAMPLE 174a & b (-)-5,6-Methylenedioxy-1S*-(3S*-phenylpyrrolidino-1-methyl) tetralinmethanesulfonate and(+)-5,6-Methylenedioxy-1R*-(3S*-phenylpyrrolidino-1-methyl) tetralinhydrochloride

Using (+)-3S*-phenylpyrrolidine and the procedures described in Examples4 and 5 but replacing 2-thiopheneacetic acid with the product of Example142 afforded a mixture of enantiomerically pure diastereomers.Chromatography on silica gel (elution with 20 % Et₂ O/ Hexanes,saturated with NH₃) provided Example 174a (S,S) after conversion to thecorresponding methane sulfonate salt, [α]_(D) -29.38° (c 0.565, CH₃ OH);[α]_(D) -37.11° (c 0.617, H₂ O). Anal. calcd. for C₂₂ H25NO₂.CH₃ SO₃ H:C, 64.01; H, 6.77; N, 3.24. Found: C, 63.97; H, 6.80; N, 3.21. Furtherelution provided Example 174b (S,R) which was converted to thecorresponding hydrochloride salt, [α]_(D) 19.02° (c 0.510, CH₃ OH).Overlapping fractions were resubmitted under the above conditions forrechromatography.

EXAMPLE 175

Using the procedures described in Example 132 and 133 but replacing2-thiophene carboxaldehyde with o-fluorobenzaldehyde provided the ethyl3-cyano-3-(o-fluoro)phenylpropionate. Reduction of the nitrile andcyclization was accomplished with Raney-Nickel in absolute ethanol at60° C. under 4 atm of hydrogen, to provide the desired pyrrolidinone.Reduction as described in Example 135 provided the desired product.

EXAMPLE 176a5.6-Methylenedioxy-1-(3-(o-fluorophenyl)pyrrolidino-1-methyl) tetralinmethanesulfonate

Using the product of Example 175 and the procedures described in Example4 and 5 but replacing 2-thiopheneacetic acid with the product of Example142 afforded the desired compound, m.p. 169°-170° C. Anal. calcd. forC₂₂ H₂₄ FNO₂.CH₃ SO₃ H: C, 61.45; H, 6.28; N, 3.12. Found: C, 61.52; H,6.25; N, 2.99.

EXAMPLE 176b & c5.6-Methylenedioxy-1R-(3R-(o-fluorophenyl)pyrrolidino-1-methyl) tetralinmethanesulfonate and5,6-Methylenedioxy-1R-(3S-(m-fluorophenyl)pyrrolidino-1-methyl) tetralinmethanesulfonate

Using the procedure described in Example 143a & b, chromatography of theproduct of Example 176a provided the R,R/S,S diastereomer Example 176b,m.p. 186°-187° C. (Anal. calcd. for C₂₂ H₂₄ FNO₂.CH₃ SO₃ H: C, 61.45; H,6.28; N, 3.12. Found: C, 6I.17; H, 6.26; N, 3.06) and the R,S/S,Rdiastereomer, Example 176c, m.p. 160°-162° C. (Anal. calcd. for C₂₂ H₂₄FNO₂.CH₃ SO₃ H: C, 61.45; H, 6.28; N, 3.12. Found: C, 61.50; H, 6.20; N,3.07).

EXAMPLE 177 5.6-Dihydroxy-1-tetralone

To a solution 5,6-dimethoxy-1-tetralone (100 g) in toluene (958 ml) wasadded aluminum chloride (200 g) in small portions. After the additionwas complete the reaction was heated to 80° C. and mechanically stirredfor 2 hours. The reaction was cooled and slowly poured into ice andconcentrated HCl. The resulting solids were filtered and washed withcold dilute HCl. the resulting solids were taken up into monoglyme,dried (MgSO₄), filtered, treated with charcoal, refiltered andconcentrated. The residue was co-concentrated with acetonitrile toprovide upon cooling 82.5 g of desired product as an off white solid,m.p. 191°-194° C.

EXAMPLE 178 5,6-Methylenedioxy-1-tetralone

To a solution of the product of Example 177 (30 g) in DMF (390 ml) wasadded cesium carbonate (83 g) followed by bromochloromethane (33 g) andthe resulting mixture heated to 100 ° C. and mechanically stirred for 2hours. The reaction was cooled, filtered and the solids washed withethyl acetate. The filtrate concentrated and the residue taken up intowater and toluene. The layers were separate and the aqueous layerreextracted with toluene. The extracts were combined, dried (MgSO₄),filtered, treated with charcoal, refiltered and concentrated to provide29.9 g of the desired product, m.p. 132°-136° C.

EXAMPLE 179 5-Benzyloxy-6-methoxy-1-tetralone

A mixture of the product of Example 177 (8.3 g), powdered potassiumcarbonate (10.1 g), powdered potassium bicarbonate (4.6 g) and benzylbromide (5.5 ml) in acetone (81 ml) was mechanically stirred at refluxfor 3 hours. The reaction was cooled, filtered and the solids washedwith acetone. The filtrate was concentrated and the residue taken upinto ethyl acetate, washed with 0.5 N HCl, brine, dried (MgSO₄),filtered and concentrated. Chromatography on silica gel (elution with30% Et₂ O/Hexanes) provided 5.3 g of desired 5-benzyloxy derivative and4.3 g of recovered starting material after rechromatography ofoverlapping fractions.

A mixture of the above material (5.3 g), potassium hydroxide (1.2 g) andmethyl iodide (3.1 ml) in abs. ethanol (48 ml) was heated at reflux for6 hours. The reaction was cooled and concentrated. To the resultingresidue was added water and the product extracted out with ethyl acetate(3x). The extracts were combined, washed with water, brine, dried(MgSO₄), filtered and concentrated to provide 5.58 g of desiredmaterial, m.p. 64°-64° C.

EXAMPLE 180 5-Hydroxy-6-methoxy-1-(3-phenylpyrrolidino-1-methyl)tetralin hydrochloride

To a solution of the product of Example 179 (3.62 g) in THF (13.2 ml)was added trimethylsilylcyanide (2.2 ml) followed by the addition oflithium cyanide (4.4 ml, 0.5 M in DMF). After 3 hours at roomtemperature, the reaction was concentrated and the residue partitionedbetween water and Et₂ O. The layers were separated and the aqueous phasereextracted with Et₂ O (2x). The extracts were combined, washed withwater, brine, dried (MgSO₄), filtered and concentrated to yield anorange oil. This material was dissolved into i-propanol (20 ml) andcooled to 0° C. After adding i-propanol saturated with HCl (20 ml), thereaction was stirred for 4 hours. The reaction was diluted with water(10 ml) the solid collected and dried under vacuum to provide 2.08 g ofthe unsaturated nitrile derivative. An addition 0.87 g of product couldbe obtained from the filtrate.

Using the procedures outlined in Examples 142 and 143, the 6-benzyloxyderivative was obtained. This material upon treatment with palladiumhydroxide in methanol under 1 atm of hydrogen provided the desiredmaterial after conversion to the corresponding HCl salt, m.p. 199°-201 °C. Anal. calcd. for C₂₂ H₂₇ nO₂.HCl: C, 70.67; H, 7.55; N, 3.75. Found:C, 70.92; H, 7.58; N, 3.70.

EXAMPLE 181 5-Benzyloxy-6-methoxy-1-tetralone

To a suspension of aluminum chloride (25.8 g) in methylene chloride (120ml) was added 5,6-dimethoxy-1-tetralone (10.0 g) and the resultingmixture heated at reflux for 2.5 hours. The reaction was cooled andpored into ice/ con. HCl and diluted with methylene chloride. The phaseswere separated and the aqueous phase reextracted with methylenechloride. The extracts were combined washed with 1-N-HCl, brine, dried(MgSO₄), filtered and concentrated to provide 4.5 g of the 6-methoxyderivative.

The above material (4.4 g) and potassium hydroxide (1.6 g) in abs.ethanol (150 ml) was heated to reflux. To this mixture was addeddropwise benzyl bromide (3.3 ml) and the reaction allowed to stir atreflux for 3 hours. The reaction was concentrated, water added and theproduct extracted with ethyl acetate (2x). The extracts were combinedwashed with 1-N-NaOH, brine, dried (MgSO₄), filtered and concentrated toprovide 5.33 g of desired product.

EXAMPLE 182 5-hydroxy-6-methoxy-1-(3-phenylpyrrolidino-1-methyl)tetralin hydrochloride

Using the procedures in Example 180 but replacing the product of Example179 with the product of Example 181, provided the desired compound, m.p.214°-215° C. Anal. calcd. for C₂₂ H₂₇ NO₂. HCl: C, 70.67; H, 7.55; N,3.75. Found: C, 70.39; H, 7.41; N, 3.69.

EXAMPLE 183

5,6-Methylenedioxy-1-(3-(p-fluorophenyl)pyrrolidino-1-methyl) tetralinmethanesulfonate

Using 3-(p-fluorophenyl)pyrrolidine (prepared from p-fluorobenzaldehydeutilizing the procedures described in Example 175) and the proceduresdescribed in Example 4 and 5 but replacing 2-thiopheneacetic acid withthe product of Example 142 afforded the desired compound, m.p. 177°-179°C. Anal. calcd. for C₂₂ H₂₄ FNO₂. CH₃ SO₃ H: C, 61.45; H, 6.28; N, 3.12.Found: C, 61.51; H, 6.58; N, 3.00.

EXAMPLE 1845,6-Methylenedioxy-1-(3-(m-methoxyphenyl)-pyrrolidino-1-methyl) tetralinhydrochloride

Using 3-(m-methoxyphenyl)pyrrolidine (prepared fromm-methoxybenzaldehyde utilizing the procedures described in Example 175)and the procedures described in Example 4 and 5 but replacing2-thiopheneacetic acid with the product of Example 142 afforded thedesired compound, m.p. 212°-213° C. Anal. calcd. for C₂₃ H₂₇ NO₃. HCl:C, 68.73; H, 7.02; N, 3.48. Found: C, 68.23; H, 7.09; N, 3.46.

EXAMPLE 1855,6-Methylenedioxy-1-(3-(o-methoxyphenyl)-pyrrolidino-1-methyl tetralinhydrochloride

Using 3-(o-methoxyphenyl)pyrrolidine (prepared fromo-methoxybenzaldehyde utilizing the procedures described in Example 175)and the procedures described in Example 4 and 5 but replacing2-thiopheneacetic acid with the product of Example 142 afforded thedesired compound, m.p. 179°-180° C. Anal. calcd. for C₂₃ H₂₇ NO₃.HCl.1/4H₂ O: C, 67.97; H, 7.07; N, 3.45. Found: C, 67.64; H, 6.94; N,3.43.

EXAMPLE 1865,6-Methylenedioxy-1-(3-(p-methoxyphenyl)-pyrrolidino-1-methyl) tetralinhydrochloride

Using 3-(p-methoxyphenyl)pyrrolidine (prepared fromp-methoxybenzaldehyde utilizing the procedures described in Example 175)and the procedures described in Example 4 and 5 but replacing2-thiopheneacetic acid with the product of Example 142 afforded thedesired compound, m.p. 152°-153° C. Anal. calcd. for C₂₃ H₂₇ NO₃. CH₃SO₃ H: C, 62.45; H, 6.77; N, 3.04. Found: C, 62.23; H, 6.71; N, 2.99.

EXAMPLE 187 5-Methoxy-1-(3-phenylpyrrolidino-1-methyl) tetralin methanesulfonate

Using 3-phenylpyrrolidine and the procedures described in Examples 4 and5 but replacing 2-thiopheneacetic acid with the product of Example 145afforded the desired compound, m.p. 158°-159° C. Anal. calcd. for C₂₂H₂₇ NO.HCl.1/2 H₂ O: C, 64.76; H, 7.56; N, 3.28. Found: C, 64.98; H,7.40; N, 3.30.

EXAMPLE 188

6-(N-N'-dimethylamino)-1-(3-phenylpyrrolidino-1-methyl)tetralindihydrochloride

A suspension of 10% Pd/C (0.75 g) and Example 155 in abs. methanol (245ml) containing formalin (5 ml) was stirred and room temperature under 4atm. of hydrogen. The reaction was filtered upon completion andconcentrated. The residue was taken up into ethyl acetate, washed withbrine, dried (MgSO₄), filtered and concentrated. Chromatography onsilica gel (elution with 1% EtOH/EtOAc) provided the N-N-dimethylaminoderivative, which was subjected under the conditions described inExample 5 to provide the desired product, m.p. 205°-206° C. Anal. calcd.for C₂₂ H₃₀ N₂.2 HCl: C, 67.80; H, 7.92; N, 6.88. Found: C, 67.27; H,7.86; N, 6.80.

EXAMPLE 189 6-Methylsulfonamido-1-tetralone

A mixture of 6-acetamido-1-tetralone (50 g) and 6 N HCl (400 ml) washeated at reflux for 2 hours, cooled and extracted with Et₂ O. Theaqueous phase was basified with ammonium hydroxide upon which aprecipitate formed. The solid was collected, dried under vacuum andchromatographed on silica gel (elution with CH₂ Cl₂ followed by 1% CH₃OH/CH₂ Cl₂) to provide 22.1 g of the amino derivative.

To a solution of the above amino derivative (7.0 g) in pyridine (40 ml)at 0° C. was added dropwise methanesulfonyl chloride (3.7 ml) and theresulting mixture allowed to stir at 0° C. for 45 minutes. The reactionwas then warmed to room temperature and allowed to stir for 30 minutes.The reaction was poured into ice/con. HCl, upon which a precipitateformed. The solid was collected to afford 9.11 g of the desiredcompound.

EXAMPLE 190 6-Methylsulfonamido-1,2,3,4-tetrahydro-1-naphthylenecarboxylic acid

Reaction of the product of Example 189 under the conditions described inExamples 1 and 142 provided the desired product.

EXAMPLE 191 6-Methylsulfonamido-1-(3-phenylpyrrolidino-1-methyl)tetralin hydrochloride

A mixture of the product of Example 190 (1.7 g) in thionyl chloride (30ml) was heated at reflux for 1 hour. The was cooled, concentrated andco-concentrated with toluene. To a solution of the resulting acidchloride in methylene chloride (30 ml) was added dropwise a solution of3-phenylpyrrolidine (1.02 g) in methylene chloride (10 ml) containingtriethylamine (2.6 ml) at 5° C. After 1 hour at 5° C., the reaction wasallowed to warm to room temperature and stir over night. The reactionwas concentrated, diluted with water and extracted with methylenechloride (2 x). The extracts were combined, washed with 1 N NaOH, 1NHCl, brine, dried (MgSO₄), filtered and concentrated. Chromatography ofthe residue on silica gel (elution with 2% CH₃₀ H/CH₂ Cl₂) afforded 1.84g of material which was subjected to the conditions outlined in Example5 to provide 0.8 g of the desired product, m.p. 139°-142° C. Anal.calcd. for C₂₂ H₂₈ N₂ O₂ S.HCl: C, 62.77; H, 6.94; N, 6.65. Found: C,62.40; H, 7.04; N, 6.56.

EXAMPLE 192 6-(N-Methyl methylsulfonamido)-1-tetralone

To a suspension of sodium hydride (1.17 g) in DMF (50 ml) at 0° C. wasadded the product of Example 189 (9.0 g) in DMF (50 ml) and theresulting mixture allowed to stir for 30 minutes. The reaction was thentreated with methyl iodide (2.5 ml) and allowed to stir at roomtemperature over night. The reaction was poured into ice water uponwhich a solid precipitated. The solid was collected, washed with waterand Et₂ O to provide 8.0 g of the desired material.

EXAMPLE 193 6-(N-methylmethylsulfonamido)-1-(3-phenylpyrrolidino-1-methyl)tetralinhydrochloride

Using the procedures outlined in Examples 1, 142 and 190 with theproduct of Example 192, provided the desired material, m.p. 195°-197° C.Anal. calcd. for C₂₃ H₃₀ N₂ O₂ S.HCl: C, 63.50; H, 7.18; N, 6.44. Found:C, 63.42; H, 7.13; N, 6.41.

EXAMPLE 194 5,6-Ethylenedioxy-1-(3-(o-fluorophenyl)pyrrolidino-1-methyl)tetralin hydrochloride

Using 3-(o-fluorophenyl)pyrrolidine and the procedures described inExamples 4 and 5 but replacing 2-thiopheneacetic acid with the productof Example 169 afforded the desired compound.

EXAMPLE 195 1,2,3,4-Tetrahydro-5,6-methylenedioxy-8-methyl-1-naphthylenecarboxylic acid

Commencing with 5,6-dimethoxy-8-methyl-1-tetralone, the desired materialwas obtained following the conditions described in Examples 177, 178, 1and 142.

EXAMPLE 196 5,6-Methylenedioxy-8-methyl-1-(3-phenylpyrrolidino-1-methyl)tetralin hydrochloride

Using 3-phenylpyrrolidine and the procedures described in Examples 4 and5 but replacing 2-thiopheneacetic acid with the product of Example 194afforded the desired compound.

EXAMPLE 197 5,6-Methylenedioxy-8-methyl-1-(3-(o-fluorophenyl)pyrrolidino-1-methyl) tetralin hydrochloride

Using 3-(o-fluorophenyl)pyrrolidine and the procedures described inExamples 4 and 5 but replacing 2-thiopheneacetic acid with the productof Example 195 afforded the desired compound.

EXAMPLE 198 5,6-Methylenedioxy-1-(3-(3,4-methylenedioxyphenyl)pyrrolidino-1-methyl) tetralin hydrochloride

Using 3-(3,4-methylenedioxyphenyl)pyrrolidine (prepared from piperonalutilizing the procedures described in Example 175) and the proceduresdescribed in Examples 4 and 5 but replacing 2-thiopheneacetic acid withthe product of Example 142 afforded the desired compound.

EXAMPLE 200 5,6-Methylenedioxy-1-(3-(2,3-methylenedioxyphenyl)pyrrolidino-1-methyl) tetralin hydrochloride

Using 3-(2,3-methylenedioxyphenyl)pyrrolidine (prepared from2,3-methylenedioxybenzaldehyde utilizing the procedures described inExample 175) and the procedures described in Examples 4 and 5 butreplacing 2-thiopheneacetic acid with the product of Example 142afforded the desired compound.

EXAMPLE 201 5,6-Methylenedioxy-1-(3-(o-methylphenyl)pyrrolidino-1-methyl) tetralin hydrochloride

Using 3-(o-methylphenyl)pyrrolidine (prepared from o-tolualdehydeutilizing the procedures described in Example 175) and the proceduresdescribed in Examples 4 and 5 but replacing 2-thiopheneacetic acid withthe product of Example 142 afforded the desired compound.

EXAMPLE 201 5,6-Methylenedioxy-8-fluoro-1-(3-(o-methylphenyl)pyrrolidino-1-methyl)tetralin hydrochloride

Using 3-(o-methylphenyl)pyrrolidine (prepared from o-tolualdehydeutilizing the procedures described in Example 175) and the proceduresdescribed in Examples 4 and 5 but replacing 2-thiopheneacetic acid withthe product of Example 159 afforded the desired compound.

EXAMPLE 202 5,6-Methylenedioxy-8-methyl-1-(3-(o-methylphenyl)pyrrolidino-1-methyl) tetralin hydrochloride

Using 3-(o-methylphenyl)pyrrolidine (prepared from o-tolualdehydeutilizing the procedures described in Example 175) and the proceduresdescribed in Examples 4 and 5 but replacing 2-thiopheneacetic acid withthe product of Example 195 afforded the desired compound.

EXAMPLE 203 5,6-Methylenedioxy-8-fluoro-1-(3-(o-fluorophenyl)pyrrolidino-1-methyl) tetralin hydrochloride

Using the product of Example 175 and the procedures described inExamples 4 and 5 but replacing 2-thiopheneacetic acid with the productof Example 159 afforded the desired compound.

The compounds were assessed for alpha-adrenergic receptor subtypeselectivity by use of radioligand binding techniques as describedpreviously (DeBernardis et. al. J. Med. Chem. 28, 1398 (1985)). Affinityfor the alpha 1 receptor was assessed using rat liver homogenates andthe radioligand [³ H]-prazosin; whereas for the alpha 2 receptor, ratcerebral cortices and the radioligand [³ H]rauwolscine were utilized.Results obtained from the binding studies are shown in Table 1 for arepresentative sample of compounds disclosed herein, showing clearly theexcellent affinity for the alpha 2 receptor, as well as the high degreeof selectivity relative to the alpha-1-adrenoceptor.

                  TABLE 1                                                         ______________________________________                                        Radioligand Binding Data at alpha-1 and                                       alpha-2 Adrenoceptors for Representative                                      Compounds                                                                              K.sub.i (nM)                                                                              alpha-2 - Selectivity                                    Example #  alpha-1  alpha-2  K.sub.i alpha 1/K.sub.i alpha-2                  ______________________________________                                         5         580      0.8      725                                               6b        1180     5.0      236                                               6d        500      1.5      333                                               6f        2160     6.5      332                                               6h        1505     3.5      430                                               7         565      1.6      353                                               11 (HCl salt)                                                                           254      1.7      149                                               12        1208     5.0      242                                               22        695      1.3      535                                               23        445      1.7      262                                               26        175      0.6      292                                               27        525      2.0      263                                               30        470      4.0      118                                               34        330      2.6      127                                               36        655      6.9       95                                               37        645      3.7      174                                               41        950      2.9      326                                               42        1050     6.6      159                                               43        1400     6.0      233                                               44        590      5.6      105                                               49        1125     10.0     113                                               58        1830     18.0     102                                               67        1170     6.0      195                                               68        1175     6.0      196                                               69        1275     13.0      98                                               70        525      5.0      105                                               82        495      4.0      124                                               83        955      8.0      119                                               85        260      1.5      173                                               86        495      3.0      165                                               87        444      1.6      278                                               88        315      2.0      158                                              114        725      5.7      127                                              115        530      3.0      177                                              121         95      1.0       95                                              128        855      8.0      107                                              129        198      3.6       55                                              141        880      4.8      183                                              143a        51      1.2       43                                              144        245      1.2      204                                              146        170      4.9       35                                              148        126      6.5       19                                              149        220      4.9       45                                              151        177      2.5       71                                              152         51      4.8       11                                              153         58      8.6       7                                               156        125      6.0       21                                              164        954      3.7      258                                              165        462      3.5      132                                              166        603      4.5      134                                              167        357      4.2       85                                              168        823      6.6      125                                              176a        79      0.6      132                                              188        118      0.5      236                                              193        121      1.3       93                                              Rauwolscine                                                                              392      4.2       93                                              ______________________________________                                    

The ability of compounds of the invention to inhibit biogenic amineuptake is determined as outlined below.

UPTAKE INHIBITION PROCEDURE

a. Synaptosomal Preparation

Sprague-Dawley derived rats of either sex, weighing about 180-250 g,were killed by decapitation. The brains were immediately removed, placedon a glass plate chilled over crushed ice and dissected according to amodification of the method of Glowinski and Iversen (J. Neurochem. 13,655-669, 1966). First, the rhombencephalon was separated by transversesection and discarded. The remaining tissue was bisected by a midlinesagittal cut. The hypothalamus was removed using the anterior andposterior reference points, respectively. The hippocampus was peeledaway and discarded and the striata were exposed and removed. Frontalcortical tissue was dissected from remaining brain structures. Thehypothalamus and striatum each weighed about 100 mg , the striata 50-75mg, and the cortex weighed up to 800 mg. The tissues were placed in acold Potter-Elvehjem glass homogenizer with 5 (cortex) or 10(hypothalamus) and 20 (striatum) volumes of ice-cold 0.32M sucrose, pH7.0 and homogenized by hand. The homogenate was centrifuged at 2500 rpmin a GLC centrifuge for 10 minutes in a refrigerated room. Thesupernatant fraction containing the synaptosomes was decanted, mixedthoroughly, and kept on crushed ice for use in the uptake studies.

b. Uptake Studies

Uptake studies were conducted according to the method of Synder andCoyle (J. Pharmacol. Exp. Ther. 165, 78-86, 1969) with minormodifications. Usually a 0.1 ml aliquot of the synaptosomal preparationwas incubated in a mixture of 0.75 ml of modified Krebs-Ringer buffer,0.05 ml of the drug being evaluated for uptake inhibition, and 0.1 ml ofa 1 μM tritiated amine (norepinephrine, serotonin or dopamine) solution(final concentration 0.1 μM) for a total volume of 1 ml. The modifiedKrebs-Ringer bicarbonate buffer used in these studies contained 118 mMNaCl, 4 mM KCl, 1.3 mM CaCl₂, 1.12 mM KH₂ PO₄, 1.2 mM MgSO₄ and 24 mMNaHCO₃, with the addition of 5 mM glucose, 0.15 mM disodium EDTA, 12.5μM pargyline and 1 mM ascorbic acid. Uptake was initiated by theaddition of the tritiated amine, and the mixture was incubated at 37° C.in a Dubnoff Metabolic Shaking Incubator for 4 minutes. Controlincubations without the test drug were conducted at 37° C. to determinetotal uptake and non-specific binding at 0° C. to correct for thediffusion of the tritiated amine into the synaptosomes and/or binding.Filtration was used to terminate uptake and collect the synaptosomes. Inthe filtration technique the incubation mixture was diluted with 4 ml ofice-cold 0.9% NaCl and filtered through GF/B glass microfiber filters(Whatman) under gentle vacuum. The filters were subsequently washed fourtimes with 5 ml of ice-cold 0.9% NaCl and transferred to glassscintillation vials. Soluene® (500 ml) and IONIC FLUOR (Packard)scintillation fluid (3.5 ml) were added and the vials were placed in amechanical shaker for 1 hour. All samples were cold and dark adapted andcounted in a Tri-Carb® (Packard) Model 460 Liquid ScintillationSpectrometer. Corrections were automatically made for quenching by theexternal standard method and for luminescence. All results (see Table 2)are based on total radioactivity.

                  TABLE 2                                                         ______________________________________                                        Biogenic Amine Uptake Inhibition for                                          Representative Compounds                                                      IC.sub.50 (μM)                                                             Example #                                                                             Norephinephrine Serotonin                                                                              Dopamine                                     ______________________________________                                         5      1.044           5.924    6.525                                         6b     0.574           1.95     10.14                                         11     1.744           7.227    10.121                                        19     0.498           0.411    6.09                                          20c    1.583           0.161    9.17                                          30     0.624           1.34     8.08                                          34     0.365           2.20     9.40                                          41     0.200           2.277    6.030                                         44     0.357           3.294    8.64                                          72     0.137           0.466    6.83                                          73     0.336           0.840    8.43                                         143a    1.101           4.027    8.718                                        160     0.991           1.844    2.929                                        165     0.398           1.238    6.674                                        166     1.524           0.400    8.770                                        176a    1.557           2.83     7.31                                         Imipramine                                                                            0.346           0.778    125.00                                       ______________________________________                                    

The results of this assay indicate that the compounds inhibit the uptakeof biogenic amines. For comparative purposes, a standard biogenic amineuptake inhibitor (imipramine) is illustrated.

The compounds of the invention can be administered in any effectivepharmaceutically acceptable form to warm blooded animals, e.g., in oral,parenteral or infusable dosage forms, or as a buccal or nasal spray.Suitable parenteral routes of administration include, for example,intramuscular, intravenous, intraperitoneal or subcutaneousadministration of the compounds.

In addition to the active compounds, compositions according to thisinvention for parenteral injection may comprise pharmaceuticallyacceptable sterile aqueous or nonaqueous solutions, suspensions oremulsions. Examples of suitable nonaqueous carriers, diluents, solventsor vehicles include propylene glycol, polyethylene glycol, vegetableoils, such as olive oil, and injectable organic esters such as ethyloleate.

Such compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispersing agents. They may be sterilized, forexample, by filtration through a bacteria retaining filter, or byincorporating sterilizing agents into the compositions. They can also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water, or other sterile injectable medium,immediately before use.

Solid dosaqe forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be admixed with at least one inert diluent such as sucrose,lactose or starch. Such dosage forms may also comprise, as is normalpractice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirscontaining inert diluents commonly used in the art, such as water.Besides such inert diluents, compositions may also comprise adjuvants,such as wetting agents, emulsifying and suspending agents, andsweetening, flavoring and perfuming agents.

Actual dosage levels of active ingredient in the compositions of theinvention may be varied so as to obtain an amount of active ingredienteffective to obtain a desired therapeutic response for a particularcomposition and method of administration. The selected dosage leveltherefore depends upon the desired therapeutic effect, on the route ofadministration, on the desired duration of treatment and other factors.Generally, dosage levels of about 0.1 to about 200, more preferablyabout 0.5 to about 150 and most preferably about 1 to about 125 mg ofactive ingredient per kg of body weight per day are administered orallyto a mammalian patient suffering from depression. If desired, the dailydose may be divided into multiple doses for administration, e.g., two tofour separate doses per day.

In addition to the above, the compounds of the invention can beadministered as topical compositions. These compositions are preferablyadministered as topical pharmaceutical compositions suitable forophthalmic administration, in a pharmaceutically acceptable vehicle suchas pharmaceutically acceptable sterile aqueous or nonaqueous solutions,suspensions, emulsions, ointments or solid inserts.

Examples of suitable pharmaceutically acceptable vehicles for ophthalmicadministration are water, propylene glycol and other pharmaceuticallyacceptable alcohols, sesame or peanut oil and other pharmaceuticallyacceptable vegetable oils, petroleum jelly, water solubleophthalmologically acceptable non-toxic polymers such as methylcellulose, carboymethyl cellulose salts, hydroxyethyl cellulose,hydroxypropyl cellulose; acrylates such as polyacrylic acid salts;ethylacrylates; polyacrylamides; natural products such as gelatin,alginates, pectins, tragacanth, karaya, agar, acacia; starch derivativessuch as starch acetate, hydroxyethyl starch ethers, hydroxypropylstarch; as well as other synthetic derivatives such as polyvinylalcohol, polyvinyl pyrrolidone, polyvinyl methy ether, polyethyleneoxide, carbopol and xantham gum; and mixtures of these polymers. Suchcompositions may also contain adjuvants such as buffering, preserving,wetting, emulsifying and dispersing agents. Suitable preserving agentsinclude antibacterial agents such as quaternary ammonium compounds,phenylmercuric salts, benzyl alcohol, phenyl ethanol; and antioxidantssuch as sodium metabisulfite, butylated hyhdroxyanisole and butylatedhydroxytoluene. Suitable buffering agents include borate, acetate,gluconate and phosphate buffers.

The pharmaceutical ophthalmic compositons of the invention may also bein the form of a solid insert. A solid water soluble or water swellablepolymer such as dextran, hydroxyloweralkyl dextran, carboymethyldextran, hydroxyloweralkyl cellulose, loweralkyl cellulose,carboxymethyl cellulose, polyvinyl alcohol, dextrin, starch, polyvinylpyrrolidone and polyalkylene glycols may be used as the carrier for thedrug.

Dosage levels of the active compound in the compositions for treatingglaucoma or reducing and/or controlling intraocular pressure may bevaried so as to obtain a desired therapeutic response to a particularcomposition. Generally, the active compound will be administered as anisotonic aqueous solution of from about 0.00001 to about 1.0 (w/v)percent concentration. More preferably, the active compound will beadministered as an isotonic aqueous solution of from about 0.00001 toabout 0.3 (w/v) percent concentration.

The term "controlling intraocular pressure" as used herein means theregulation, attenuation and modulation of increased intraocular tension.The term also means that the decrease in the otherwise elevatedintraocular pressure obtained by the methods and compositons of theinvention is maintained for a significant period of time as, forexample, between consecutive doses of the composition of the invention.

The effect on intraocular pressure of the compounds of the invention canbe determined in rabbits by using the following method.

EFFECTS OF TOPICALLY ADMINISTERED COMPOUNDS ON INTRAOCULAR PRESSURE OFRABBITS

a. Method

The intraocular pressure lowering effects of the compounds wereevaluated in unanesthetized, male albino, New Zealand rabbits weighing2.0 to 2.5 kg. The rabbits were placed in Plas Labs restraining devicesfor the duration of the experiment. Intraocular pressure (IOP) wasmeasured with a Bausch and Lomb Applamatic Tonometer and recorded as theaverage of three individual readings at each time point in theexperiment. Baseline IOP values were established at three time pointsseparated by 30 minutes. Each compound or vehicle was applied topicallyto the cornea in a volume of 0.1 ml to one eye in each six rabbits. Thecontralateral eye was untreated. IOP was recorded at 5, 15, 30, 60 and90 minutes after dosing. The results obtained show that the compoundsare able to reduce intraocular pressure in vivo.

b. Results

    ______________________________________                                        % Change in Intraocular Pressure After Treatment                              (0.3% soln.) Compared to Untreated Eye in Rabbits                             Compound of                                                                              (Minutes)                                                          Example    5        15     30      60   90                                    ______________________________________                                        Vehicle     +1       +7     -3     +13   +9                                   10         -45      -31    -25     -36  -23                                   11 (HCl salt)                                                                            -38      -55    -54     -44  -20                                   ______________________________________                                    

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

What is claimed is:
 1. ##STR11## wherein R₁ is selected from the groupconsisting of hydrogen, halo, lower alkyl, lower alkoxy, thioalkoxy;andR₂ is lower alkoxy; R₃ and R₄ are independently selected fromhydrogen, hydroxy, lower alkyl, halo, and thioalkoxy; or R₁ and R₂ takentogether can form a methylenedioxy or ethylenedioxy bridge; and R₇ isphenyl, thienyl, furyl or substituted phenyl wherein the phenyl ring issubstituted with methylenedioxy, ethylenedioxy or with one or twosubstituents independently selected from lower alkyl, halo, hydroxy,lower alkoxy, amino, and thioalkoxy; ora pharmaceutically acceptablesalt thereof.
 2. 5,6-Methylenedioxy-1-(3-phenylpyrrolidino-1-methyl)tetralin or a pharmaceutically acceptable salt thereof.
 3. A compoundselected from:5,6-Methylenedioxy-1R*-(3R*-phenylpyrrolidino-1-methyl)tetralin or a pharmaceutically acceptable salt thereof; and5,6-Methylenedioxy-1S*-(3*-phenylpyrrolidino-1-methyl)-tetralin or apharmaceutically acceptable salt thereof; or a mixture of the two.
 4. Acompound selectedfrom5,6-Methylenedioxy-1R*-(3S*-phenylpyrrolidino-1-methyl) tetralin ora pharmaceutically acceptable salt thereof; and5,6-Methylenedioxy-1S*-(3R*-phenylpyrrolidino-1-methyl)-tetralin or apharmaceutically acceptable salt thereof; or a mixture of the two. 5.8-Fluoro-5,6-methylenedioxy-1-(3-phenylpyrrolidino-1-methyl) tetralin ora pharmaceutically acceptable salt thereof. 6.5,6-Methylenedioxy-1-(3R-(o-fluorophenyl)-pyrrolidion-1R-methyl)tetralin or a pharmaceutically acceptable salt thereof. 7.5,6-Methylenedioxy-1-(3S-(o-fluorophenyl)-pyrrolidion-1R-methyl)tetralin or a pharmaceutically acceptable salt thereof.
 8. A compound asdefined by claim 1 wherein R₁ and R₂ together are methylenedioxy orethylenedioxy; or a pharmaceutically acceptable salt thereof.
 9. Acompound as defined by claim 1 wherein R₇ is phenyl or substitutedphenyl wherein the phenyl ring is substituted with methylenedioxy,ethylenedioxy or with one or two substituents independently selectedfrom lower alkyl, halo, hydroxy, lower alkoxy, amino, and thioalkoxy; ora pharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition for selectively inhibiting α₂ adrenergic receptorscomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound of the formula: ##STR12## wherein R₁ isselected from the group consisting of hydrogen, halo, lower alkyl, loweralkoxy, thioalkoxy; andR₂ is lower alkoxy; R₃ and R₄ are independentlyselected from hydrogen, hydroxy, lower alkyl, halo, and thioalkoxy; orR₁ and R₂ taken together can form a methylenedioxy or ethylenedioxybridge; and R₇ is phenyl, thienyl, furyl or substituted phenylwhereinthe phenyl ring is substituted with methylenedioxy, ethylenedioxyor with one or two substituents independently selected from lower alkyl,halo, hydroxy, lower alkoxy, amino, and thioalkoxy; ora pharmaceuticallyacceptable salt thereof.
 11. A pharmaceutical composition for treatingdepression comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of the formula: ##STR13##wherein R₁ is selected from the group consisting of hydrogen, halo,lower alkyl, lower alkoxy, thioalkoxy; andR₂ is lower alkoxy; R₃ and R₄are independently selected from hydrogen, hydroxy, lower alkyl, halo,and thioalkoxy; or R₁ and R₂ taken together can form a methylenedioxy orethylenedioxy bridge; and R₇ is phenyl, thienyl, furyl or substitutedphenyl wherein the phenyl ring is substituted with methylenedioxy,ethylenedioxy or with one or two substituents independently selectedfrom lower alkyl, halo, hydroxy, lower alkoxy, amino, and thioalkoxy;ora pharmaceutically acceptable salt thereof.
 12. The composition ofclaim 11 wherein the compound is selectedfrom:5,6-Methylenedioxy-1R*-(3R*-phenylpyrrolidino-1-methyl) tetralin ora pharmaceutically acceptable salt thereof; and5,6-Methylenedioxy-1S*-(3S*-phenylpyrrolidino-1-methyl)-tetralin or apharmaceutically acceptable salt thereof; or a mixture of the two.
 13. Apharmaceutical composition for inhibiting biogenic amine uptakecomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound of the formula: ##STR14## wherein R₁ isselected from the group consisting of hydrogen, halo, lower alkyl, loweralkoxy, thioalkoxy; andR₂ is lower alkoxy; R₃ and R₄ are independentlyselected from hydrogen, hydroxy, lower alkyl, halo, and thioalkoxy; orR₁ and R₂ taken together can form a methylenedioxy or ethylenedioxybridge; and R₇ is phenyl, thienyl, furyl or substituted phenyl whereinthe phenyl ring is substituted with methylenedioxy, ethylenedioxy orwith one or two substituents independently selected from lower alkyl,halo, hydroxy, lower alkoxy, amino, and thioalkoxy; ora pharmaceuticallyacceptable salt thereof.
 14. A method for selectively inhibitingalpha-2-adrenergic receptors comprising administering to a patient inneed a therapeutically effective amount of a compound of the formula:##STR15## wherein R₁ is selected from the group consisting of hydrogen,lower alkyl, lower alkoxy, halo, and thioalkoxy; andR₂ is lower alkoxy;R₃ and R₄ are independently selected from hydrogen, hydroxy, loweralkyl, halo, and thioalkoxy; or R₁ and R₂ taken together can form amethylenedioxy or ethylenedioxy bridge; and R₇ is phenyl, thienyl, furylor substituted phenyl wherein the phenyl ring is substituted withmethylenedioxy, ethylenedioxy or with one or two substituentsindependently selected from loweralkyl, halo, hydroxy, lower alkoxy,amino and thioalkoxy; ora pharmaceutically acceptable salt thereof. 15.A method of treating depression comprising administering to a patient inneed, a therapeutically effective amount of a compound of the formula:##STR16## wherein R₁ is selected from the group consisting of hydrogen,halo, lower alkyl, lower alkoxy, thioalkoxy; andR₂ is lower alkoxy; R₃and R₄ are independently selected from hydrogen, hydroxy, lower alkyl,halo, and thioalkoxy; or R₁ and R₂ taken together can form amethylenedioxy or ethylenedioxy bridge; and R₇ is phenyl, thienyl, furylor substituted phenyl wherein the phenyl ring is substituted withmethylenedioxy, ethylenedioxy or with one or two substituentsindependently selected from lower alkyl, halo, hydroxy, lower alkoxy,amino, and thioalkoxy; ora pharmaceutically acceptable salt thereof. 16.A method for inhibiting biogenic amine uptake comprising administeringto a patient in need a therapeutically effective amount of a compound ofthe formula: ##STR17## wherein R₁ is selected from the group consistingof hydrogen, halo, lower alkyl, lower alkoxy, thioalkoxy; andR₂ is loweralkoxy; R₃ and R₄ are independently selected from hydrogen, hydroxy,lower alkyl, halo, and thioalkoxy; or R₁ and R₂ taken together can forma methylenedioxy or ethylenedioxy bridge; and R₇ is phenyl, thienyl,furyl or substituted phenyl wherein the phenyl ring is substituted withmethylenedioxy, ethylenedioxy or with one or two substituentsindependently selected from lower alkyl, halo, hydroxy, lower alkoxy,amino, and thioalkoxy; ora pharmaceutically acceptable salt thereof.